**1. Introduction**

Recently, it has been shown that both the responses to placebo and antidepressant increased [1]. Kirsch has claimed that pharmaceutical companies did not include mildly and moderately depressed patients in trials of efficacy after finding that these patients did not benefit beyond placebo [2]. He consistently insists that antidepressants are not more effective than placebos in moderately depressed patients [3]. Drug-placebo differences are considered to be small in efficacy trials, and most of the response to antidepressants seems due to expectancy [3].

Major depressive disorder is one of the most common psychiatric disorders which is burdensome and costly worldwide in adults. Although pharmacological and non-pharmacological treatments are available, because of inadequate resources, antidepressants are used more frequently than psychological interventions.

By using a meta-analysis, all antidepressants were shown more efficacious than placebo in adults with major depressive disorder. Smaller differences between active drugs were found when placebo-controlled trials were included in the analysis [4].

Serotonin (5-HT) has been indicated to be involved in etiology of depression [5]. The roles of various metabolites of kynurenine (KYN) pathway are reviewed [6], so we do not discuss these roles in detail.

As to relationships between serotonin levels and depression, we analyzed plasma levels of TRP metabolites in patients of depression.

Although the concentration of 5-HT has been considered to be low in depressive patients [7], 5-HT concentration in the brains of suicide victims were not low [8]. Therefore, it is not known if 5-HT concentration is decreased in the brains of depressive patients.

We have recently succeeded in simultaneous measurements of TRP metabolites in plasma using an ultrahigh-speed liquid chromatography/mass spectrometry (LC/ MS) [9–12].

We now report age and gender differences of various TRP metabolites in patients of major monopolar depression and healthy volunteers.
