Evidence for the role of norepinephrine in depression:

Reserpine lowers norepinephrine levels

Monoamine Oxidase (MAO) inhibitors increase the supply of norepinephrine in many neurons and at the same time alleviate symptoms of depression

Another type medication used to treat depression, the tricyclics, also increase norepinephrine supplies (Snyder, 1984; 1976).

Because norepinephrine belongs to the class of chemicals called catecholamines this is known as the catecholamine theory.

Problems with the catecholamine theory

Reserpine also lowers the levels of serotonin in the brain

MAO inhibitors and the tricyclics raise serotonin levels as well as norepinephrine (Amsterdam et al, 1980)

This led many researchers to believe that low levels of serotonin may also cause unipolar depression (Golden & Gilmore, 1990). This is known as the indolamine theory, as serotonin belongs to the class of chemicals known as indolamines.

There are a number of possibilities regarding the biochemical contributions to unipolar depression:

Low norepinephrine + Low serotonin = depression

Low serotonin or low norepinephrine = depression

Neither low serotonin, nor low norepinephrine lead to depression.

Is Depression caused by both low norepinephrine and low serotonin?

The blood pressure medicine “Aldomet” which lowers norepinephrine levels, but not serotonin levels leads to depression in some people (Comer, 1995). This suggests that it is not necessary to have both low norepinephrine and low serotonin levels to develop depression.

Is Depression caused by either low norepinephrine or low serotonin?

There is a considerable amount of research that supports the theory that for some people depression is caused by low norepinephrine and that for others, low serotonin. For example, MHPG, a metabolite of norepinephrine is excreted in low levels in some, but not all depressed people (Yazici et al, 1993; Maas, 1975). Similar results have been found with 5-HIAA a major metabolite of serotonin (Yazici et al, 1993; Maas, 1975).

Another line of research involves administering precursors of serotonin or norepinephrine to depressed participants. If they alleviate the symptoms it would support the theory. Van Praag (1984) found that tryptophan, a precursor of serotonin, does indeed reduce symptoms of depression in some, but not all cases. Similarly, Gelenberg et al (1980) found that tyrosine, a precursor of norepinephrine, alleviates depressive symptoms in some cases.

There is also evidence that norepinephrine depression is different to serotonin depression. Indeed, serotonin and norepinephrine are very different chemically and the structures that contain the structures that use these neurotransmitters are also different. Asberg et al (1976) found that depressed participants whose serotonin was depleted were more apathetic and suicidal than those whose norepinephrine was depleted. Suicide attempts by those with low serotonin were more frequent and more violent than those whose serotonin was not depleted. Some researchers, however, believe that it is not the supply of these neurotransmitters that is responsible for unipolar depression; they believe that ineffective norepinephrine and serotonin receptors are responsible for depression and this creates the illusion of a low supply (Newman et al, 1993).

Is Depression caused by something else other than low serotonin or low norepinephrine?

Other researchers believe that other neurotransmitters, such as acetylcholine may be involved in depression: exposure to insecticides that increase acetylcholine levels causes some adults to become depressed (Gershon & Shaw, 1961). Also, Intravenous administration of physostigmine, which increases acetylcholine supplies, can cause depression in previously nondepressed participants (Risch et al, 1983). It is, of course possible that an overall imbalance between norepinephrine, serotonin and acetylcholine causes symptoms of unipolar depression (Ballenger, 1988).

Evaluation of neurotransmitter theories

Much of the research that has led to the development of these theories has involved chemically generating depression like symptoms in laboratory animals; it may be incorrect to infer that these symptoms are akin to human depression (Overstreet, 1993). Nevertheless, the studies quoted above did involve human participants.

Another difficulty is that many of the studies measured neurotransmitter activity indirectly. It was assumed, for example, that precursors such as tryptophan were converted into neurotransmitters such as serotonin after administration, which in turn increased the activity of that chemical in the brain. Moreover, measurement of neurotransmitter metabolites in urine was believed to reflect neurotransmitter activity in the brain; however, this is not necessarily the case.

Another problem with these neurotransmitter theories of depression is that recent studies have shown that antidepressants are only effective if the brain is able to create new neurons. The therapeutic action of antidepressants may not, therefore, be directly due to their action on neurotransmitter levels. The study also explains why it takes several weeks or months for antidepressants to alleviate the symptoms of depression.

Also, it is not certain whether neurotransmitter activity is a cause or an effect of depression. cognitive theorists, for example, suggest that faulty cognitions precede low neurotransmitter activity and depression, while the biological position claims the opposite. Research has so far failed to confirm either position; negative cognitions can lower the activity of serotonin and norepinephrine, and low levels of these neurotransmitters can cause negative cognitions (Comer, 1995).