Alas, Poor Noradrenaline

Previously I posted about the much-maligned serotonin theory of depression and tentatively defended it, while making it clear that "low serotonin" was certainly not the whole story. Critics have noted that the serotonin-is-happiness hypothesis has become folk wisdom, despite being clearly incomplete, and this is generally ascribed to the marketing power of the pharmaceutical industry. What's also interesting is that a predecessor and rival to the serotonin hypothesis, the noradrenaline theory, failed to achieve such prominence.

Everyone's heard of serotonin. Only doctors and neuroscientists have heard of noradrenaline (called norepinephine if you're American), which is another monoamine neurotransmitter. Chemically the two molecules are rather different, but they both play roughly parallel roles in the brain, in the sense that both are released from a small number of cells originating in the brain stem onto areas throughout the brain in what's often described as a "sprinkler system" arrangement.

Forty years ago, noradrenaline was seen by most psychopharmacologists as being the key chemical determinant of mood, and the leading theory on the cause of depression was some kind of noradrenaline deficiency. At this time, serotonin was generally seen as being at best of uncertain importance. In 1967 two superstars of psychopharmacology, Joseph Schildkraut and Seymour Kety, wrote a review article in Science in which they summarized the evidence for a noradrenaline theory of depression. It still makes quite convincing reading, and since 1967, more evidence has come to light; reboxetine, which selectively inhibits the reuptake of noradrenaline, is at least as effective as Prozac, which is selective for serotonin. Although it's slightly controversial, it also seems as though antidepressants which target both monoamines are slightly more effective than those which only target either.

So what happened to the noradrenaline theory? If pressed, most experts will admit that there must be something in it, and it is still discussed - but noradrenaline just doesn't get talked about as much as serotonin in the context of depression and mood. So far as I can see there is little good reason for this - given that both serotonin and noradrenaline seem to be involved in mood, the best thing would be to study both, and in particular to study their interactions. Yet this is not what most scientists are doing. Noradrenaline has just dropped off the scientific radar.

Because everyone likes graphs, and because I had nothing better to do today, I knocked together a couple to show the rise and fall of noradrenaline. The first shows the total number of PubMed entries for each year from 1969 to 2007, containing hits in the Title or Abstract for [noradrenaline OR norepinephrine] AND [depression OR depressive OR antidepressant OR antidepressants OR antidepressive] vs. [Serotonin OR 5HT OR 5-hydroxytryptamine] AND [depression OR depressive OR antidepressant OR antidepressants OR antidepressive]. As you can see, the two lines track each other very closely until about 1990, when interest in serotonin in the context of depression / antidepressants suddenly takes off, leaving noradrenaline languishing far behind.

What's fascinating is that the total amount of published research about noradrenaline also peaked around 1990 and has since declined markedly, while publications about serotonin and dopamine (another monoamine neurotransmitter) have been steadily growing.

What happened around 1990? Prozac, the first commercially successful selective serotonin reuptake inhibitor (SSRI), was released onto the U.S. market in late 1987. Bearing in mind that science generally takes a year or so to make it from the lab to the journal page, it's tempting to see 1990 as the year of the onset of the "Prozac Effect". Prozac notoriously achieved a huge amount of publicity, far more than was granted to older antidepressants such as imipramine, despite its probably being less effective. Could this be one reason why serotonin has eclipsed noradrenaline in the eyes of scientists?

A couple of caveats: All I've shown here are historical trends, which is not in itself proof of causation. Also, the fall in the total number of publications mentioning noradrenaline is much too large to be directly due to the stall in the number of papers about noradrenaline and depression / antidepressants. However, there could be indirect effects (scientists might be less interested in basic research on noradrenaline if they see it as having no relevance to medicine.)

Note 16/12/08: I've realized that it would have been better to include the term "5-HT" in the serotonin searches as this is a popular way of referring to it. I suspect that had I done this the serotonin lines would have been higher, but the trends over time would be the same.

J. J. Schildkraut, S. S. Kety (1967). Biogenic Amines and Emotion Science, 156 (3771), 21-30 DOI: 10.1126/science.156.3771.21