Serotonin and depression

This post is an attempt at summarising and explaining a paper called 5-HT and depression: is the glass half full? Authored by Trevor Sharp and Philip J. Cowen which was published in Current Opinion in Pharmacology, 2011 volume 11 pages 45–51.

The theory that abnormally low levels of the neurotransmitter serotonin (also called 5-hydroxytryptamine, 5-HT) can cause depression is now 50 years old.

The theory arose when it was noticed that depressed patients had low serotonin levels in cerebrospinal fluid, and also that the first effective antidepressant drugs had the effect of increasing the amount of serotonin in the gap between neurons (the synaptic cleft). Since then the old tricyclic antidepressants have been replaced with medications that more accurately target serotonin, the selective serotonin re-uptake inhibitors’ (SSRIs) which have fewer adverse effects and tend to be more effective at relieving depression symptoms.

Despite the progress since 1967, up to half of the patients prescribed antidepressants do not get enough relief from their symptoms, and pharmacologists still don’t clearly understand how changes in serotonin translate to altered mood.

That 5-HT (serotonin) is associated with mood and depression has been shown by pharmacological studies and also positron emission tomography (PET) studies looking at the distribution of 5-HT receptors in the brains of depressed patients. Other studies have shown that artificially restricting dietary intake of the amino L-tryptophan can cause a return of depression symptoms in patients with a history of depression. This is significant because L-tryptophan is the precursor (chemical building block) of 5-HT. Similar L-tryptophan depletion in people who have a high family incidence of depression but themselves have not had depression caused a less severe lowering of mood.

Genetic components

Depression does run in families, with a moderate to high heritability (heritability is a measure of how likely a trait is inherited, low means less likely and high indicates it is more likely to be inherited in a population).

One particular gene, slc6a4, which codes for the 5-HT transporter protein, has been well studied. Levels of the 5-HT transporter can vary by up to sevenfold within the general population. Individuals with low levels of this 5-HT transporter have increased risk of depression when associated with stressful life events. The region of this gene where it is regulated (i.e., the volume control’) is rich in methylation sites which can result in semi-permanent changes to gene expression as a result of environmental influences (such as a stressed or depressed mother during pregnancy, stressful events, childhood trauma).

Neuronal Repair

Current thinking is that increased synaptic 5-HT activates a downstream gene programme that leads to enhanced neuronal plasticity which has failed because of the adverse effects of stress and other environmental and genetic factors.

In effect, some sort of stress derails the ongoing repair and maintenance of brain circuitry’ which can be overcome by bumping up serotonin levels in neurons.

This idea of serotonin enabling improved neuronal plasticity in depressed patients dovetails nicely with ideas of how psychological treatments (such as counselling, CBT, DBT) function to help treat depression. Psychotherapists help a patient to reframe situations and learn more positive ways to view situations. With increased serotonin levels enabling neural repair and realignment of neural pathways, learning is facilitated and so the therapy and drug treatment work together.

Up next 100 day project As I dug through my notes in Evernote yesterday I found one about the 100 Day Project. The basic idea is to commit to creating something new Becoming a better faith blogger The PDF for today is one I downloaded as a freebie for subscribing to Ed Cyzewski’s blog a few years back. I’ve followed his blog on and off since
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