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Understanding depression and anxiety
Understanding depression and anxiety

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4.3 Tryptophan depletion experiments

While the monoamine hypothesis still underlies the treatment of depression, researchers now consider that, in its original form at least, it is too simplistic to explain the complex aetiology of depression.

The hypothesis postulates that low levels of monoamines cause depression, and as we have seen in Section 4.2, there appears to be some evidence for this. However investigations into the link between monoamine levels and depression were typically carried out on people who were depressed at the time.

  • Why might this be a problem when studying, for instance, serotonin levels in depressed people?

  • Because cause cannot be distinguished from effect. Low serotonin levels in depressed people could be a cause of depression, but they could also be a result of depression. Or some unknown, third factor could underlie both depression and low serotonin levels.

Researchers have since tried to clarify the relationship between low monoamine levels and depression experimentally, by depleting the levels of monoamines in the brains of participants.

Serotonin is manufactured in the body from a chemical commonly found in the diet; the amino acid tryptophan. Tryptophan is found in protein-rich foods, including meat, eggs, cheese and soybeans.

By feeding participants a special, otherwise well-balanced, diet free of tryptophan it is possible to reduce serotonin levels in their brains. The levels of the other monoamines, noradrenalin and dopamine, can also be depleted using similar techniques. Amino acids are the building blocks of proteins. Proteins are molecules that contribute to the structure and functioning of all our cells, including our neurons.

The findings of a meta-analysis by Ruhé et al. (2007) on the results of studies of monoamine depletion are summarised in Table 1. (A meta-analysis is discussed in the related OpenLearn course Emotions and emotional disorders [Tip: hold Ctrl and click a link to open it in a new tab. (Hide tip)] .) The groups listed in Table 1 are:

  • Group 1 – healthy participants who do not, and have never had, major depression (MD), and have no family history of MD
  • Group 2 – Healthy participants who do not, and have never had, MD, but do have a family history of MD
  • Group 3 – Patients in remission from MD who are not currently taking antidepressants
  • Group 4 – Patients in remission from MD who are currently taking antidepressants.
Table 1  Reaction to monoamine depletion.
Group 1Group 2Group 3 Group 4
Depletion of tryptophan/serotoninNo lowering of mood Slightly lowered mood Moderate decrease in mood Induced relapse in those taking antidepressants that affect the serotonin system (such as SSRIs and SNRIs)
Depletion of noradrenalin/dopamine levels No lowering of mood Slightly lowered mood No lowering of mood (no studies were available in this category)

Activity 8 Serotonin levels and mood

Timing: Allow 5 minutes

Do any of these results (Table 1) suggest that lowering serotonin levels causes a lowering of mood or results in depression?


Patients in remission from MD who were taking antidepressants such as SSRIs and SNRIs that affect the serotonin system (Group 4) were likely to have a relapse if tryptophan/serotonin was depleted. Patients in remission from MD, but who were not currently taking antidepressants (Group 3) were also likely to experience low mood if serotonin was depleted. Participants (Group 2) who had a family history of depression showed slightly lowered mood. Thus lowering serotonin levels can have an effect on mood, albeit to different extents.

However, healthy participants without a personal or family history of major depression (Group 1) showed no mood changes, so serotonin depletion did not lower mood in everyone.

Overall, therefore, the results in Table 1 do not suggest a direct or consistent link between monoamine levels and major depression.

Activity 9 Analysing tryptophan depletion

Timing: Allow 10 minutes

Booij et al. (2002), also analysed studies on tryptophan depletion, showed that (a) having had previous depressive episodes, (b) being female, (c) having had treatment with an SSRI, and (d) having a history of suicidal thoughts or attempts, were all strong predictors of whether tryptophan depletion (and hence serotonin depletion) would depress mood.

Consider Booij et al.’s suggestions above. Do any of them chime with any of the findings shown in Table 1?


Yes, (a) is consistent with the lowering of mood of patients in Group 3 and Group 4; (c) is consistent with the relapse of patients in Group 4.

One possibility is that a depressive episode changes the serotonin system in some way, making a person more vulnerable to the effects of future changes in serotonin levels. A related possibility is that a subgroup of those with depression have a vulnerability or diathesis, due to their genetic make-up, that affects the workings of the serotonin system, making them particularly susceptible to depression when serotonin levels are depleted.

Is there any information in Table 1 which might fit in with this?


Yes – the finding that people in Group 2, who have not experienced major depression themselves but have a family history of depression, experience some lowering of mood following serotonin depletion.

To conclude, tryptophan-depletion experiments suggest that serotonin depletion has some effects on mood, but that there is no simple relationship between levels of monoamines and depression.

The next section considers an even more significant problem with the monoamine hypothesis, one that has fuelled much research and has led to a more sophisticated chemical and molecular hypothesis for the aetiology of depression.