**3. Discussion of part 1**

The availability of endogenous 5-HT as a neurotransmitter is crucial in many physiological processes. Serotonergic neurons in the central nervous system are involved in regular behavioral states and physiological processes including arousal,

**139**

were nearly related.

blood [22].

controls.

*Studies on Tryptophan Metabolites in Patients of Major Monopolar Depression*

sleep, appetite, pain, releases of hormone, and mood. Dysfunction of 5-HT neurons

Many scientific research has been done to know roles of 5-HT in pathophysiol-

Since pathological changes are investigated in the brain and cerebrospinal fluid of suicides, it is claimed that 5-HT neurotransmission is implicated in the causes of suicide [13, 14]. Low levels of 5-HIAA in cerebrospinal fluid were shown in suicide attempters of depression [15]. Although the brainstem of suicide attempters had less 5-HT and 5-HIAA, most postmortem studies report no differences in cortical

Furthermore [17] patients with MDD have been reported to have higher 5-HIAA in jugular venous blood and have been argued to reflect higher brain 5-HT neuro-

We simultaneously analyzed plasma levels of TRP metabolites in healthy people and patients of MMD. As shown in **Tables 2** and **3**, significant age and gender dif-

It is difficult to speculate reasons of such changes in MMD. Probably, hormonal

These results suggest that much attention has to be paid to age and gender if we

Statistical differences of TRP metabolites between MMD or BD and healthy

As stated above, serotonin (5-HT) plays roles in a state of depression since selective inhibitors of the uptake of 5-HT and the blockers of 5-HT 1A receptors are

There is some evidence indicating that in patients of affective disorders, the

We have shown that plasma levels of 5-HT were very low in patients of depression, but the levels of 5-HIAA or KYN were not different from the levels of control persons suggesting that 5-HT was immediately converted to 5-HIAA in patients of depression [9]. Due to the presence of 5-HT transporter in platelet membranes, most of 5-HT are believed to be stored in platelets in the

We have shown that whole blood 5-HT concentration showed marked changes throughout daytime, with maximum values in the evening and lowest values in the

So we wanted to measure 5-HT levels in the blood of patients of depression and

We examined at five timepoints whole blood 5-HT levels in depressive patients of Hamamatsu University Hospital and control volunteers. The number of depres-

Patients were in depressive states as confirmed by a mean score of 18.7 (range 12–24) on the 24-item scale of Hamilton depression rating scale [24]. None of them were administered with any drug except for small doses of benzodiazepines, for at

Blood levels of 5-HT were measured using HPLC as described by Anderson et al [25]. Analytical recoveries were 85% (SD 4.5%, CV 5.6%). Amount and response

morning, whereas its metabolite 5-HIAA followed contrary [23].

**3.1 The diurnal variation of 5-HT in the blood of patients of depression**

*DOI: http://dx.doi.org/10.5772/intechopen.91967*

5-HT or 5-HIAA of suicides [16].

transmission and turnover [18].

changes may be implicated.

people will be reported elsewhere.

effective in its treatment [19, 20].

sive patients was 18 and 30 volunteers.

least 10 days before blood was taken.

regulation of circadian rhythms is disturbed [21].

ferences disappear in patients of MMD.

ogy of depression.

may lead to depression and other mental disorders.

So the roles of 5-HT in depression is still confusing.

want to analyze TRP metabolites, especially 5-HT and 5-HIAA.

### *Studies on Tryptophan Metabolites in Patients of Major Monopolar Depression DOI: http://dx.doi.org/10.5772/intechopen.91967*

sleep, appetite, pain, releases of hormone, and mood. Dysfunction of 5-HT neurons may lead to depression and other mental disorders.

Many scientific research has been done to know roles of 5-HT in pathophysiology of depression.

Since pathological changes are investigated in the brain and cerebrospinal fluid of suicides, it is claimed that 5-HT neurotransmission is implicated in the causes of suicide [13, 14]. Low levels of 5-HIAA in cerebrospinal fluid were shown in suicide attempters of depression [15]. Although the brainstem of suicide attempters had less 5-HT and 5-HIAA, most postmortem studies report no differences in cortical 5-HT or 5-HIAA of suicides [16].

Furthermore [17] patients with MDD have been reported to have higher 5-HIAA in jugular venous blood and have been argued to reflect higher brain 5-HT neurotransmission and turnover [18].

So the roles of 5-HT in depression is still confusing.

We simultaneously analyzed plasma levels of TRP metabolites in healthy people and patients of MMD. As shown in **Tables 2** and **3**, significant age and gender differences disappear in patients of MMD.

It is difficult to speculate reasons of such changes in MMD. Probably, hormonal changes may be implicated.

These results suggest that much attention has to be paid to age and gender if we want to analyze TRP metabolites, especially 5-HT and 5-HIAA.

Statistical differences of TRP metabolites between MMD or BD and healthy people will be reported elsewhere.

### **3.1 The diurnal variation of 5-HT in the blood of patients of depression**

As stated above, serotonin (5-HT) plays roles in a state of depression since selective inhibitors of the uptake of 5-HT and the blockers of 5-HT 1A receptors are effective in its treatment [19, 20].

There is some evidence indicating that in patients of affective disorders, the regulation of circadian rhythms is disturbed [21].

We have shown that plasma levels of 5-HT were very low in patients of depression, but the levels of 5-HIAA or KYN were not different from the levels of control persons suggesting that 5-HT was immediately converted to 5-HIAA in patients of depression [9]. Due to the presence of 5-HT transporter in platelet membranes, most of 5-HT are believed to be stored in platelets in the blood [22].

We have shown that whole blood 5-HT concentration showed marked changes throughout daytime, with maximum values in the evening and lowest values in the morning, whereas its metabolite 5-HIAA followed contrary [23].

So we wanted to measure 5-HT levels in the blood of patients of depression and controls.

We examined at five timepoints whole blood 5-HT levels in depressive patients of Hamamatsu University Hospital and control volunteers. The number of depressive patients was 18 and 30 volunteers.

Patients were in depressive states as confirmed by a mean score of 18.7 (range 12–24) on the 24-item scale of Hamilton depression rating scale [24]. None of them were administered with any drug except for small doses of benzodiazepines, for at least 10 days before blood was taken.

Blood levels of 5-HT were measured using HPLC as described by Anderson et al [25]. Analytical recoveries were 85% (SD 4.5%, CV 5.6%). Amount and response were nearly related.

*Melatonin - The Hormone of Darkness and Its Therapeutic Potential and Perspectives*

**138**

**Table 3.**

**3. Discussion of part 1**

*TRP metabolite levels of patients of MMD.*

The availability of endogenous 5-HT as a neurotransmitter is crucial in many physiological processes. Serotonergic neurons in the central nervous system are involved in regular behavioral states and physiological processes including arousal,

#### **Figure 2.**

*Diurnal variation of blood serotonin levels of healthy men and patients of major depression. Ordinate, blood levels of 5-HT; abscissa, time when blood was taken. \*\*p < 0.01 control vs. depression, \*0.05, levels at 8:30 vs. 10.30 of depressive patients.*

As shown in **Figure 2**, whole blood 5-HT levels were significantly lower in depressed patients at 8:30 10:30, 12:30, and 14:30. The blood concentration of 5-HT showed a circadian variation.

In the group of depression, the lowest value was shown at 8:30 and the level progressively increased to 14:30.

### **4. Discussion of part 2**

Platelet 5-HT content is most likely regulated by the platelet transport activity. Variations of 5-HT uptake in depressed patients have been reported by several groups [26–28].

Seasonal changes of serotonin (5-HT) uptake in blood platelets from depressed patients and normal controls were studied over a 2-year period to know if seasonal variations were present [26]. A measure of the number of 5-HT uptake sites in normal controls and depressed patients was significantly higher in fall and winter than in spring and summer. The number of 5-HT uptake in the depressed patients was lower than in normal controls throughout the year. Normal controls showed lower number in April and June. A similar trend was present in the depressed patients but the lowest values were found in the month of December.

Blood levels of melatonin, 5-HT, cortisol, prolactin, and serotonin uptake by platelets were measured at 08:00 to 08:00 hours of the following day in healthy men in age from 27 to 35 years [27]. The active transport of 5-HT by platelets was shown to be significantly correlated with melatonin blood levels. This finding suggests either a direct effect of melatonin on 5-HT active transport or the influence of the suprachiasmatic nucleus on serotonin uptake by platelets.

So far depressive disorders are considered to be associated with various neurobiological alterations like hyperactivity of the hypothalamic-pituitary-adrenal axis, altered neuroplasticity, and altered circadian rhythms. Unfortunately, the causal

**141**

Japan

*Studies on Tryptophan Metabolites in Patients of Major Monopolar Depression*

connections between depressive disorders and disturbed circadian rhythms have not been completely clarified. Chronobiological therapy is based on these disturbed processes. For the treatment of the circadian symptoms, various scientifically tested chronotherapeutics are available with different effectiveness and evidence like light therapy or sleep deprivation. The successful treatment of depression also frequently

Further studies of circadian variation of 5-HT system may help to understand

, Akikazu Takada4

2 Department of Psychiatry, Northern Yokohama Hospital, Showa University, Japan

3 Global Application Development Center, Shimadzu Corporation, Kanagawa-ken,

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

1 Department of Psychiatry, School of Medicine, Showa University, Japan

4 International Projects on Food and Health (NPO), Tokyo, Japan

\*Address all correspondence to: takadaa@mwd.biglobe.ne.jp

provided the original work is properly cited.

\* and Akira Iwanami1

the control of serotonergic nervous system and the treatment of depression.

*DOI: http://dx.doi.org/10.5772/intechopen.91967*

**Abbreviations**

**Author details**

TRP tryptophan 5-HT serotonin

KYN kynurenine XA xanthurenic acid AA anthranilic acid KNA kynurenic acid 3-HKN 3-hydroxykynurenine IDO indoleamine dioxygenase TDO tryptophan dioxygenase

5-HIAA 5-hydroxyindoleacetic acid IAA indole-3-acetic acid

SSRI selective serotonin uptake inhibitor SNRI serotonin epinephrine reuptake inhibitor CGI-S clinical global impression—severity scale

SDS self-rating depression scale HDRS Hamilton depression rating scale

Hiroi Tomioka1,2, Junichi Masuda3

leads to an improvement in altered circadian rhythm.

*Studies on Tryptophan Metabolites in Patients of Major Monopolar Depression DOI: http://dx.doi.org/10.5772/intechopen.91967*

connections between depressive disorders and disturbed circadian rhythms have not been completely clarified. Chronobiological therapy is based on these disturbed processes. For the treatment of the circadian symptoms, various scientifically tested chronotherapeutics are available with different effectiveness and evidence like light therapy or sleep deprivation. The successful treatment of depression also frequently leads to an improvement in altered circadian rhythm.

Further studies of circadian variation of 5-HT system may help to understand the control of serotonergic nervous system and the treatment of depression.
