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 What Happens in the Brain

Few physicians would accept that depression is purely a biochemical phenomenon. Many other factors are thought to contribute; biological and genetic factors, personality traits and life events may all contribute. In addition, there are a number of psychological theories about the aetiology of depression. Perhaps the greatest areas of agreement about depression are that:

  • the condition is complex(heterogeneous)
  • there is no one explanation of its cause
  • there is no single treatment that will be effective in all cases.

What Happens in the Brain

The areas of the brain implicated in depression are the forebrain and the limbic system.

Many structures of the forebrain appear to be involved in depression, although it is not certain if disturbances to these brain areas cause depression, or if they are simply affected in the course of the disease. The brain areas involved include the frontal and temporal lobes of the forebrain, the basal nuclei, and parts of the limbic system including the hippocampus, amygdala and the cingulate gyrus. The cerebral cortex controls thinking and it is likely that abnormalities in this part of the forebrain are responsible for the negative thoughts that are typical of depression.

The hypothalamus and the pituitary gland may also play a role in depression, as they are involved in hormonal control, and increased levels of some hormones may play a role in maintaining a depressed state.

If the body is placed under stress, the hypothalamus-pituitary-adrenal axis becomes activated. The hypothalamus produces corticotropin releasing factor (CRF) which is hypothesised to play a role in the precipitation of certain forms of depression. CRF stimulates the pituitary gland to secrete adrenocorticotropic hormone, which in turn stimulates the adrenal glands to release cortisol. Cortisol depresses mood and approximately 50% of people with severe depression have raised cortisol levels.

In the brainstem, the raphe nuclei and the locus coeruleus are involved in the transmission of signals to other parts of the brain, and are likely to be involved in depression. An imbalance or deficiency of the neurotransmitters, serotonin, noradrenaline and dopamine are implicated in depression, although it may be a change in receptor function, and not neurotransmitter concentration, that causes depression.


The monoamine theory suggests that depression is caused by a deficiency in monoamine-dependent neurotransmission. This theory was first developed in the 1950s, following the observation that treatment with the drug reserpine (antihypertensive drug; no longer available in many countries) could induce depression. It was found subsequently that the mechanism of action of reserpine was to deplete neurons of their monoamine neurotransmitters such as serotonin and noradrenaline (Kaplan et al., 1994). Arguably, this situation would result in a shortage of monoamines, so preventing or reducing neurotransmission in serotonergic or noradrenergic neurons. Further support for the theory was obtained when the early antidepressant drugs became available and their mechanisms of action were discovered.

  • Tricyclic (TCAs) and tetracyclic antidepressants inhibit the reuptake of monoamines from the synapse after transmission. They affect the reuptake of both noradrenaline and serotonin, with certain differences between the various TCAs available. For example, agents such as clomipramine affect the reuptake of serotonin more than the reuptake of noradrenaline, while agents such as amitriptyline affect noradrenaline and serotonin about equally and other TCAs affect noradrenaline more than serotonin.

  • Monoamine oxidase inhibitors (MAOIs) inhibit monoamine oxidase, one of the enzymes responsible for serotonin and noradrenaline breakdown. They affect levels of both noradrenaline and serotonin.

Most psychiatrists recognise that biochemical changes occur in depression and that these can be prompted or further modified by psychosocial factors. The balance of such factors in an individual may provide the clues to successful management with a combination of drugs and psychosocial therapy.

The Role of Serotonin

In depression, symptoms frequently involve functions such as mood and emotional behaviour, sleep and hormonal activity, which are controlled by serotonergic neurons. Intuitively, it seems likely that disturbance of serotonin activity plays a role in the causation of depression.

There is evidence from autopsies of people who have died by suicide that serotonin levels are lower than usual in people with depression. Such evidence is far from conclusive, however, since there are a number of similar studies with contradictory findings.

In practice, the principal evidence that serotonin is involved in depression stems from the finding that drugs which selectively affect serotonin are very effective in the treatment of the condition. Selective serotonin reuptake inhibitors (SSRIs) are effective antidepressants that have a potent inhibitory effect on the reuptake of serotonin but very little effect on the reuptake of other monoamines or on other neurotransmitter receptors.

It seems likely, however, that noradrenaline is involved in depression as well. Anatomically, the serotonergic and noradrenergic neurons are closely linked. It has been suggested that the selective inhibition of serotonin reuptake also works partly through a 'knock-on' effect on noradrenaline.

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The Role of Receptor Responses

Interest is growing in the possible role played by changed receptor responses in depression. However, there is more to depression than a simple shortage of neurotransmitters.

"Upregulation" is a term used for the hypothesis that depression may be associated with an overall increase in the number of postsynaptic receptors. There is a theory that the effect of this would be to increase the amount of monoamine that would be needed in order to produce a response.

The occurrence of upregulation has proved difficult to demonstrate in depressed patients, but there is evidence that antidepressant treatment tends to reduce receptor numbers - this effect of antidepressants is sometimes known as receptor downregulation. The phenomenon is now quite well-documented for SSRIs, TCAs and MAOIs, as well as for the physical treatment electroconvulsive therapy (ECT).

An alternative suggestion is that antidepressants bring about an increase in the sensitivity of postsynaptic receptors, so that reduced levels of neurotransmitter can produce a response that is closer to normal. Another theory is that depression increases the sensitivity of the presynaptic autoreceptors that moderate monoamine release via a feedback mechanism. As a result less of the neurotransmitter needs to be released before production is 'switched off'.


Factors contributing to depression:





Life events

Social factors

Family tendency to depression


Poor housing


Losing one's job

An unhappy marriage


Long-term illness

Financial worries




Possible causes of secondary depression:

Other psychiatric disorders

Drug abuse

Chronic, painful or serious medical illness






Anxiety disorders


Parkinson's disease

Antirheumatics NSAIDs (e.g. aspirin)

Eating disorders






Heart disease



Last updated: 20.12.2011





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