Neurotransmitters and Depression

Noradrenaline Hypothesis | Serotonin Hypothesis

There are many theories about the aetiology of depression and some of them involve neurotransmitters. Depression seems to be linked to disturbances in brain circuits or neural pathways that convey signals with the monoamine neurotransmitters serotonin or noradrenaline. Low levels of these monoamines in certain neurones are correlated in some way with depression.

The link between monoamines and depression was made in the 1950's. Reserpine, a drug used to treat hypertension, was found to cause severe depression in 15% patients. Since this drug depletes monoamines, low levels of monoamines were therefore implicated in depression. Another drug used in the treatment of tuberculosis was found to elevate mood. This drug inhibited the breakdown of monoamines and therefore raised monoamine levels. This drug was a monoamine oxidase inhibitor (MAOI) and belonged to the first class of antidepressants.

Noradrenaline hypothesis

The catecholamine hypothesis of mood disorders was put forward in 1960's by Schildkraut. The deficiency of noradrenaline in certain brain circuits is associated with depression whilst an overabundance results in mania. These brain circuits are found in the brain stem, in the locus coeruleus, and project to many areas of the brain including the limbic system which is important in regulating emotions.

Evidence for noradrenaline depletion in depression also comes from the following observations:

  • Levels of metabolites of noradrenaline in urine and CSF are low in depressed individuals
  • Increased densities of certain noradrenaline receptors in the cortex of depressed suicide victims.
  • This pattern of 'up-regulation' occurs when the level of neurotransmitter in synapses is abnormally low and is a compensatory mechanism to pick up whatever signals are available.
  • Drugs which selectively block noradrenaline reuptake such as reboxetine , increase nor-adrenaline in synapses and are effective antidepressants in many people.


mesopontine tegmentum
dorsal raphe nucleus
nucleus locus coeruleus  


Norepinephrine Projection Pathways



Serotonin Hypothesis

Synaptic depletion of serotonin is implicated in depression. It may be that defects in neuronal circuits using serotonin could dampen
noradrenaline signalling. Serotonin producing neurones project from the raphe nuclei in the brain stem to many regions of the brain including those that secrete noradrenaline. However, serotonin may also be more directly responsible for depression since there are serotonin producing neurones extending into areas of the brain thought to be involved in depressive symptoms - these include the amygdala which is involved in apetite, libido and sleep.

Serotonin Pathways


Tricyclic antidepressants produce many effects in the brain, including a decrease in serotonin reuptake and a consequent rise in serotonin levels in synapses

Selective serotonin reuptake inhibitors (SSRI's) such as prozac, block the reuptake of serotonin into the presynaptic neurone, they are hugely significant in the treatment of depression.