Tryptophan and the Response to Selective Serotonin Reuptake Inhibitors (SSRIs)

Recent reports have indicated that some people, particularly children and adolescents, may respond to at least some SSRIs by becoming more suicidal and more impulsively violent, rather than less so.¹ There are a number of possible reasons for this. We report here the results of a rat study² which indicates that the response to an SSRI depends upon the amount of tryptophan in the circulation and, hence, upon diet (or tryptophan or 5-hydroxytryptophan supplementation).

The authors report previous animal studies in which the amount of plasma tryptophan resulted in differential responses to SSRIs. For example, in one study, acute tryptophan depletion led to a significant decrease in extracellular brain serotonin levels in rats pretreated with the SSRI fluvoxamine for 2 weeks, but not in animals that were not tryptophan-depleted.

The Sprague-Dawley rats in the new study² were randomly assigned to one of three dietary conditions: one group received a control diet with 0.24 g of tryptophan/100 g of food; another group received the same diet but with 10% of the amount of tryptophan (low tryptophan) in the control diet; and the third group received the control diet plus 200% of the tryptophan in the control diet (high tryptophan). The animals were then treated with the SSRI fluvoxamine or with fenfluramine, which causes release of serotonin, and the results were compared.

Levels of serotonin (5-HT) and 5-HIAA (a metabolite of serotonin) were significantly reduced after the low-tryptophan diet, while serotonin, but not 5-HIAA, was increased after the high-tryptophan diet. There was a trend toward an increase of serotonin release in the high-tryptophan diet as compared to controls.

The animals were tested on a task requiring differential reinforcement of low-rate responding (DRL), where the animal has to learn to wait a certain period of time (typically 72 s) after a cue to push a lever for a reward. This is used as a behavioral screening test in rodents for antidepressant activity. Note that low levels of serotonin, present in many cases of human depression, result in impaired impulse regulation; we would expect, therefore, that (as it appears to work the same in rats) animals with low levels of serotonin would have trouble controlling, for such a long period of time, their impulse to push the lever.

The authors report, “The effect of the TRP [tryptophan] high diet on DRL performance in the present study is similar to the effect of oral fluvoxamine administration of 20 mg/kg, suggesting that TRP supplementation may have antidepressant potential. It is of note in this respect that the increase in extracellular 5-HT [serotonin] following a TRP high diet in this study is in the same order of magnitude as the 5-HT increase following oral administration of 30 mg/kg of fluvoxamine observed previously in our laboratory.”³(Emphasis added.) So, surprise, surprise, tryptophan supplementation alone has an antidepressant potential, something that was noted by hundreds of thousands, possibly millions, of people before the FDA effectively banned tryptophan dietary supplements by prohibiting tryptophan imports and (in our opinion, no coincidence) paved the way for the rise of the SSRIs.

The authors conclude: “… the findings of this study suggest that nutritional factors play an important role in the biosynthesis of 5-HT. Increasing 5-HT levels by increasing the availability of TRP might augment the therapeutic efficacy of SSRIs, whereas malnutrition may render patients refractory to SSRI treatment.” This is something that needs to be followed up in the case of depressed children and teenagers. It may be that those responding the “wrong” way to SSRIs are those with low plasma tryptophan levels and that, with adequate plasma tryptophan levels, some will do better on lower doses of the drugs or may not even need antidepressant drugs at all.

1. For example, see Check, “Bitter pills.” Nature 431:122-4 (2004). In this article, some psychiatrists are said to blame a side effect called akathisia, an agitated state that can occur in a minority of patients on antidepressants. However, this is just placing a label on the problem rather than an explanation. In fact, low plasma serotonin levels can induce what is called agitated depression. It is interesting to note that Wyeth, the maker of the SSRI Effexor^®, warned doctors in August 2003 about the link to suicidal thoughts in young patients, based on findings in clinical trials (and added the warning to its label), but was forced by the FDA to withdraw the warning because that was not the official FDA position at that time! Once again, FDA censorship puts lives at risk. See Mathews, “Congress to air controversies over drug trials,” The Wall Street Journal, Sept. 8, 2004, pp B1, B9.
2. van der Stelt et al. Effects of dietary tryptophan variations on extracellular serotonin in the dorsal hippocampus of rats. Psychopharmacology 172:137-44 (2004).
3. Bosker et al. Effects of single and repeated oral administration of fluvoxamine on extracellular serotonin in the median raphe nucleus and dorsal hippocampus of the rat. Neuropharmacology 34:501-8 (1995).