What is the Monoamine Hypothesis of Depression?

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What Causes Depression?

There are various competing and sometimes overlapping theories that aim to explain mood disorders such as depression. The biological model, and the one that most closely guides the kinds of medication supplied for depression, is that psychological problems are caused by one or more problems in the brain. In depression the focus of attention is generally around genetic predisposition, hormones and neurology. In the case of neurology, too little of one or more neurotransmitters at the synapse is thought to affect mood, which is the basis of the monoamine hypothesis of depression.

The Monoamine Group

There’s little doubt that drugs like fluoxetine (Prozac) have helped in the awareness of serotonin and it’s also true that much of the research into neurotransmitters has focused on the role of serotonin, specifically the lack of it, as a key agent in depression. Despite this, the actual biological theory is based around three neurotransmitters known as the monoamine group; namely serotonin, dopamine and norepinephrine.

The Monoamine Hypothesis

The monoamine hypothesis of depression states that a depletion of neurotransmitters, known as monoamines, within the brain leads to depression. This depletion may be related to a lack of neurotransmitters or some other fault. For example, people with major depressive disorder may also have fewer monoamine nerve receptors, or possibly less sensitive receptors than people without depression. The effect would be the same as a low level of neurotransmitters. As much as depression may be caused by an undersupply of neurotransmitters other mood disorders, for example mania, are presumed to be caused by an oversupply of neurotransmitters.

Serotonin and norepinephrine are examples of monoamines. Within the body another monoamine called monoamine oxidase has the effect of breaking down both serotonin and norepinephrine. Therefore, so the theory goes, by blocking the effect of the monoamine oxidase, the number of monoamines in the brain increases and symptoms of depression are relieved. A class of drugs known as monoamine oxidase inhibitors (MAOI), of which phenelzine (Nardil) is one example, have this effect.

The Development of Antidepressant Medications

The monoamine theory actually developed from something of a happy accident. During the testing of a drug called imipramine, originally aimed at relieving the symptoms of tuberculosis, and subsequently reducing psychotic symptoms in schizophrenia, researchers noticed a marked antidepressant effect.

By the 1950s, two classes of medication were introduced, the tricyclic antidepressants (so called because of their chemical structure) and MAOIs. It was not until 1987 that a second generation of antidepressants with a different chemical structure was introduced. We call this second generation of drugs selective serotonin reuptake inhibitors (SSRIs); now one of the most frequently prescribed class of drugs for depression.

Side Effects of MAOIs

MAOIs not only inhibit the production of monoamine oxidase in the brain, they also prevent its production in the liver and intestines where it breaks down tyramine. Tyramine is an amino acid, which if allowed to build up, can result in a sudden and potentially fatal rise in blood pressure leading to stroke. In this sense MAOIs are unique in that they have potentially life threatening side effects. The ingestion of any food, drink or drugs that contain tyramine is therefore potentially fatal. Tyramine is found in certain (mainly red) wines, marmite, bananas, cheeses, smoked or pickled fish.


Field, A. (2003) Clinical Psychology. Crucial Publishing.

McBride, P., Brown, R.P., DeMeo, M., & Keilp, J (1994). The relationship of platelet 5-HT-sub-2 receptor indices to major depressive disorder, personality traits, and suicidal behaviour. Biological Psychiatry, 35, 295-308.

Mills, K.C. (2004) Monoamine oxidase inhibitors. In: Tintinalli JE, Kelen GD, Stapczynski JS, Ma OJ, Cline DM, eds. Tintinalli’s Emergency Medicine: A comprehensive Study Guide. 6th ed. New York: McGraw-Hill:160.