Measurement of brain regional α-[11C]methyl-L-tryptophan trapping as a measure of serotonin synthesis in medication-free patients with major depression

Context: The serotonin hypothesis of depression invokes a relative or absolute deficit of serotonin neurotransmission. Reduced synthesis of serotonin in the brain pathways mediating the expression of mood (ie, the limbic cortex) is a plausible candidate mechanism. Objectives: To measure and compare, using the alpha-[C-11]methyl-L-tryptophan/positron emission tomography method, the brain trapping constant of alpha-[C-11] methyl-L-tryptophan (K*, milliliters per gram per minute), an index of serotonin synthesis, in brain areas involved in the regulation of mood in patients with major depression (MD) and age- and sex-matched controls. Design: Between-group comparison. Setting: Department of Psychiatry and Montreal Neurological Institute, McGill University. Participants: Seventeen medication-free outpatients with a current episode of MD (9 women: mean +/- SD age, 41 +/- 11 years; 8 men: mean +/- SD age, 41 +/- 11 years) and 17 controls (9 women: mean +/- SD age, 37 +/- 15 years; 8 men: mean +/- SD age, 32.5 +/- 9.9 years). Main Outcome Measure: Normalized K*, normalized to the global mean, was measured in the dorsolateral prefrontal, anterior cingulate, and mesial temporal cortices; the thalamus; and the caudate nucleus. Results: Compared with age- and sex-matched controls, normalized K* was significantly decreased bilaterally in female patients with MD in the anterior cingulate cortex, in the left anterior cingulate cortex in male patients with MD, and in the left mesial temporal cortex in male and female patients with MD (P < .001 for all). Exploratory analyses identified additional patient-control differences for normalized K* (eg, inferior frontal gyrus and superior parietal lobule), most of which, once corrected for 38 multiple comparisons, lost their significance. Morphometric measurements of the cingulate cortex divisions confirmed that the reduction of normalized K* in depressed patients was not attributable to a reduction in gray matter volume. Normalized K* in the anterior cingulate cortex did not correlate with ratings of depression severity collected at the time of scan. Conclusions: Reduction of normalized K*, an index of serotonin synthesis, in parts of the limbic and paralimbic cortices may contribute to the biochemical alterations associated with MD.