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2005, Number 6

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Salud Mental 2005; 28 (6)

The serotoninergic system and depression. Part one.

Moreno J, Campos MG, Lara C, Torner C

Language: Spanish
References: 58
Page: 20-26
PDF size: 76.08 Kb.


ABSTRACT

According to Spitzer et al., depression is a mood disorder characterized by sadness and accompanied by other symptoms such as irritability, anxiety, significant weight/appetite loss or gain, and feelings of guilt, worthlessness and hopelessness. Depressed patients are unable to accomplish everyday activities and may develop thoughts of death or suicide.
Different neurotransmitters have been involved in the pathogenesis of depression; among them are noradrenaline, dopamine, gamma-aminobutyric acid, neuropeptides such as vasopressin and somatostatin, and endogenous opioids. However, serotonin (5-HT) has been the most studied and is suggested to play a central, but not exclusive, role in depression. This review analyzes studies which have involved serotonin as the vulnerable biochemical factor in depression.

Postmortem studies

Postmortem studies and 5-HT and 5-hydroxy-indolacetic acid quantification
Many researchers have reported a decrease in 5-HT or its metabolite 5-hydroxy-indolacetic acid (5-HIAA) concentration in the brain stem of suicidal people. However, results are inconsistent since in other cerebral regions, such as the hypothalamus, cingulate and frontal cortex, no 5-HT or 5-HIAA concentrations have been found.
Validity of postmortem results is limited by methodological issues as postmortem interval length, age of subjects, lack of assessment of nutritional status of suicide victims, drug abuse, medication, and differences in psychiatric diagnosis.

Serotonin transporter and post-mortem studies
Serotonin transporters are localized in cell presynaptic membranes in raphe and serotoninergic terminals projected to brain cortex.
Radioligand studies have shown the occurrence of high affinity binding sites for [3H]-imipramine in human brain. Because of their localization in serotoninergic terminals and their likely participation in depression pathology, these binding sites have been suggested to be depression biomarkers.
Early studies reported a decrease in [3H]-imipramine binding to prefrontal cortex in suicide victims with previous depression, as well as in occipital cortex and hippocampus in depressed patients who died of natural causes. These findings have been confirmed by other compound studies including [3H]-citalopram which has been identified as a more selective ligand for the serotonin transporter.
A review by Purselle and Nemeroff of studies correlating depression, serotonin and suicide behavior found ambiguous data. These were likely due to methodological deficiencies such as a small sample size, deficient pairing criteria for control and treated groups, differences in radioligands, as well as disregarding comorbidity. These differences limit validation, comparison and interpretation of study results.

Serotonin receptors and postmortem studies
5-HT1A receptors. A decrease in 5-HT1A receptor density has been reported in suicidal depressed victims in the hippocampus, an important brain area for cognitive function. However, this receptor is highly sensitive to antidepressant treatment, which makes its determination rather ambiguous. On the other hand, no significant difference in brain cortex 5-HT1A receptors has been found between non-suicidal and suicidal subjects.
5-HT1D receptors affinity has been reported to be decreased in depressed patients. 5-HT2 receptors. Several researchers have observed an increase in postsynaptic 5-HT2 receptors in the frontal cortex and amygdala in suicidal depressed victims and depressed patients with no pharmacological treatment. An increase in 5-HT2A receptors has been reported in prefrontal cortex of suicidal adolescents, as well as higher levels of mRNA codifying for these receptors in prefrontal cortex and hippocampus.

Tryptophan, serotonin, melatonin and 5-hydroxy-indolacetic acid in biological fluids

Tryptophan in cerebrospinal fluid
Findings on tryptophan levels in cerebrospinal fluid are controversial, for both normal and low levels have been found in depressed patients.

Tryptophan in plasma
Using the hypothesis of a decreased tryptophan availability to explain a low serotoninergic central activity in depressed patients does not stand due to different findings in levels of plasma-free tryptophan. Lower, normal and even higher levels of free trypto-phan have been reported.
Tryptophan availability might be influenced by neutral amino acids competing to cross the blood-brain barrier. Brain tryptophan levels might be modified if the free tryptophan/neutral amino acids ratio is reduced. It has been observed that depressed patients receiving antidepressants experienced a depressive relapse after receiving a low-tryptophan diet and returned to the remission state on returning to a regular food intake. Pharmacokinetic and pharmacodynamic factors might play a role in tryptophan availability in some depressed patients.

Serotonin in cerebrospinal fluid
Serotonin levels in cerebrospinal fluid are very low; this difficult carrying out studies in depressed patients.

Serotonin in platelets
Methodological and clinical criteria may explain the controversial results on platelet serotonin levels, which have found to be increased, decreased or unchanged.

Serotonin in blood
As platelet serotonin content includes 99% blood serotonin, serotonin blood levels might reflect brain serotonin content. After using fluvoxamine, a specific serotonin-reuptake inhibitor, the serotonin concentration in whole-blood preparation of patients was strongly reduced. After treatment with an unspecific monoamine oxidase inhibitor, serotonin content was increased. Determination of 5-HT in whole blood preparation of patients treated with fluvoxamine might indicate a measure of drug compliance.

Serotonin in plasma
A significant decrease in plasma serotonin levels has been reported in depressed patients.

Melatonin in plasma
The melatonin synthesis use serotonine as building blocka. Melatonin have an important role in depression. It has been proposed that depressive states are a consequence of an inappropriate melatonin secretion. Therefore low plasmatic melatonin levels may be used as a biological marker for some types of depression.

5-HIAA in cerebrospinal fluid and plasma
5-HIAA, the major metabolite of 5-HT in plasma, has been suggested as a depression biomarker since cerebrospinal fluid 5-HIAA levels have found to be decreased in depressed patients. On the other hand, plasma 5-HIAA levels from untreated depressed patients were found to be significantly negatively correlated with severity of depression, despite the fact that the origin of plasma 5-HIAA is largely peripheral.

5-HIAA in urine
Studies concerning urine 5-HIAA levels have been inconclusive in depression, likely due to the 5-HIAA urinary level variations from one day to another. Furthermore, the major fraction of 5-HIAA in blood as an intestinal precedence, therefore, blood 5-HIAA levels may not correlate with cerebral levels.

Conclusion
The serotoninergic system seems to be the neurotransmission system whose variations may explain every clinical manifestation in depressed patients. However, interpretation of measurements of tryptophan, serotonin, and its metabolites in biological fluids as an index of brain serotonin availability and function is difficult to achieve, mainly due to methodological discrepancies.


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