The Serotonin Connection to Depression

The link between depression and low serotonin has been confirmed in a great many studies over the past 20 years. Perhaps the majority of people with depression have problems associated with low serotonin.

Tryptophan is the missing link in this equation, because it is the raw material from which the brain makes serotonin.

The research has studied the effects of low tryptophan in both healthy people and those with a personal or family history of emotional problems. People with a history of depression seem more likely to develop low moods when tryptophan is depleted. However, researchers have found that low tryptophan also causes depression in people who are healthy.

Low Tryptophan and Depression

. Low tryptophan causes low moods in healthy people

In the early research on tryptophan, a team at McGill University in Montreal evaluated the effects of tryptophan on mood. In their first study, group of healthy male subjects were given a protein drink lacking tryptophan, which lowers the level of tryptophan in the body (tryptophan depletion).

After 5 hours, these participants experienced, "significantly elevated scores on the depression scale... indicating a rapid mood lowering effect of tryptophan depletion in normal males . This effect is probably mediated by a lowering of brain serotonin. Our results suggest that low brain serotonin might be one factor precipitating depression in some patients ."

SN Young and others. " Tryptophan depletion causes a rapid lowering of mood in normal males." Psychopharmacology ( Berlin ). 1985; Vol 87, No 2: pages 173-177.

In a second study, this team also evaluated the effects of environment and mental state on mood. Their goal was to determine the degree to which tryptophan plays a role in mood. Healthy male subjects "were exposed either to a supportive and comfortable atmosphere (positive environment), or an unrewarding and unstimulating environment (negative environment). In the tryptophan depletion group the environmental manipulation did not have any influence on the mood lowering effect." [Subjects with low tryptophan were depressed regardless of whether they were in an environment that was negative or positive.]

Researchers concluded, "It may be that tryptophan depletion lowers mood in normal males because low serotonin influences mood directly rather than via cognitive [mental] processes. Our data strongly support the idea that serotonin exerts an effect on mood and that low serotonin may, in some patients, be an important factor contributing to the etiology [origin] of clinical depression.

SE Smith and others. "A test of possible cognitive and environmental influences on the mood lowering effect of tryptophan depletion in normal males." Psychopharmacology ( Berlin ). 1987; Vol 91, No 4: pages 451-457.

A third study at McGill followed up on this research, focusing on the impact of tryptophan depletion on diet and mood. Researchers observed that although participants' carbohydrate intake remained unchanged, "significantly less protein was chosen. Tryptophan depletion also caused an acute lowering of mood, suggesting that low serotonin may be involved in the etiology [origin] of clinical depression in some patients."

SN Young and others. "The effect of altered tryptophan levels on mood and behavior in normal human males." Clinical Neuropharmacology . 1988; Vol 11, Supplement 1: S207-215.

. The link between depression, low serotonin, and low tryptophan confirmed

Later studies have also monitored the effects of low tryptophan in healthy volunteers. At Maastricht University in the Netherlands , subjects were depleted of either tryptophan or lysine - two essential amino acids. Researchers found that low levels of lysine had no effect on mood, whereas low tryptophan did depress mood.

Researchers indicated that, "After 6 hours of tryptophan depletion, subjects reported significantly more tiredness and lowering of mood...and memory performance declined. After 6 hours of lysine depletion, no significant differences in mood and memory...were found. We conclude that the effects of tryptophan depletion on mood and memory are specific for the depletion of tryptophan... This supports the hypothesis that tryptophan depletion affects brain serotonin."

T Klassen and others. " Specificity of the tryptophan depletion method." Psychopharmacology . January 1999; Vol 141, No 3: pages 279-286.

At Massachusetts General Hospital in Boston , researchers studied ten patients who underwent tryptophan depletion. Their finding: "Tryptophan depletion was significantly related to increased scores on clinician-rated depression and anxiety scales and on self-rated depression, anxiety, and somatic [physical] symptoms...The mood effect of tryptophan depletion...was confirmed."

MK Spillmann and others. "Tryptophan depletion in SSRI-recovered depressed outpatients." Psychopharmacology ( Berlin ). May 2001; Vol 155, No 2: pages 123-127.

Susceptibility to Low Moods

. Effects of low tryptophan when there is a predisposition to moods

In a later study conducted at McGill University , researchers evaluated the role of tryptophan in healthy men (aged 18 to 30) with a family history of emotional illness. Participants in a second study group had no family history of emotional problems.

The results: "Six of 20 subjects with a family history of affective [emotional] illness...showed a lowering of mood. [Of the] 19 subjects without a family history of psychiatric illness, none showed a lowering of mood...Our data support the hypothesis that subjects...with family history of major emotional disorders...show a greater reduction in mood after tryptophan depletion."

C Benkelfat and others. "Mood-lowering effect of tryptophan depletion. Enhanced susceptibility in young men at genetic risk for major affective disorders." Archives of General Psychiatry . September 1994; Vol 51, No 9: 687-697.

In Stockholm , at the Institute of Clinical Neuroscience , researchers conducted a study of tryptophan depletion involving 20 patients with major depressive disorders who were currently in remission. The finding: "Five of the 12 patients showed a worsening of depressive symptoms during the day of the test. In contrast, there was no mood alteration in the eight control patients who were not tryptophan depleted...Low mood appeared to be associated with low tryptophan, the serotonin precursor."

A Aberg-Wistedt and others. "Serotonergic 'vulnerability' in affective disorder: a study of the tryptophan depletion test and relationships between peripheral and central serotonin indexes in citalopram-responders." Acta Psychiatrica Scandinavica . May 1998; Vol 97, No 5: pages 374-380.

A study at Littlemore Hospital in Oxford , England evaluated the responses to tryptophan depletion of 15 women who had suffered recurrent episodes of major depression, but had recovered. After tryptophan depletion, 10 of the 15 women experienced "temporary but clinically significant depressive symptoms." The researchers concluded, "Rapid lowering of brain serotonin function can precipitate clinical depressive symptoms in well, untreated individuals who are vulnerable to major depressive disorder."

KA Smith and others. "Relapse of depression after rapid depletion of tryptophan." Lancet . March 29, 1997 ; Vol 349, No 9056: pages 915-919.

At University of Arizona Health Sciences , 12 subjects with a history of major depressive episodes and 12 matched healthy subjects received two tryptophan depletion tests 1 week apart. Following the tests, they monitored the progress of study participants and found that those who experienced depression during the test were more likely to relapse into depression at a later time: "Follow-up analysis showed that the mood response to tryptophan depletion reliably predicts major depressive episodes during the follow-up year."

FA Moreno and others. "Tryptophan depletion and risk of depression relapse: a prospective study of tryptophan depletion as a potential predictor of depressive episodes." Biological Psychiatry . August 15, 2000 ; Vol 48, No 4: pages 327-329.