Author: marianna pasquali
Date: 31/03/2014


Serotonin definition Serotonin (5-HT, 5-hydroxytryptamine) was isolated for the first time in 1948 from gastrointestinal mucosa cells. Is a biogenic amine with low molecular weight, amonoamine neurotransmitter syntesized in serotoninergic neurons of SNCand also in the enterochromaffin cells in the GI tract. It’s main involved in regulation of mood.
The chemical formula is C 10 H 12 N 2 O.
In humans, the level of endogen serotonin is about 10 mg and, more or less the 90% of it is localized in the enterochromaffin cells, 8% in platelets and the remaining 2% is spread in the different areas of SNC, where it acts as a neurotransmitter.

Syntesis Serotonin biochemically derives from tryptophan and, for this reason, is classified as a tryptamine, anindole that is an aromatic heterocyclic organic compound. The chemical formula is
C 10 H 12 N 2

5-HT is syntesized from the essential amino acid tryptophan through a short metabolic pathway consisting of two enzymes, tryptophan hydroxylase (TPH) and amino acid decarboxylase (DDC):
# Tryptophan is actively reuptaken from nervous cells (thanks to a carrier of also other big, neutrals or ramificated chain amino acids).
# Tryptophan undergoes, first an oxydrilation on the indolic ring, then a decarboxylation of the amino acid (fig.)

The final product, 5-HT, is stored in secretory granules by a vescicular carrier; eventually it is released through exocitosis from serotoninergic neurons.

In the nervous system, the action of the 5-HT released is ended by neuronal reuptaking, done by a specific carrier Na+-dependent. This carrier is located in the membrane of the axon of serotoninergic neurons. The main metabolic pathway of the 5-HT involves the oxidative deammination done by the monoamineoxidase (MAO) forming the 5-hydroxyindolacetaldehyde; the aldehyde is transformed in 5-hydroxyindoleacetic acid (5-HIAA) by an ubiquitarian enzyme: aldeyde dehydrogenase.
Among the 30 neurotransmitters considerated, there are three of them, serotonin, norepinephrine and epinephrine,that are related to the development of the depression. Depressions are categorized for their pathogeneses, genetics, and cerebral biochimics; according to the last one, the mechanism at the base of the desease is the dysfunction of cerebral neurotransmission. Although, several studies proposed a multifactorial model of the depressive phenomenon.
Patients are treated with antidepressant drugs that influence the complessive balance of the three neurotransmitters in the structures of the brain that regulate emotions, stress reaction, sleep system, appetency, sexuality.


Selective serotonin re-uptake inhibitors or serotonin-specific reuptake inhibitor (SSRIs) are a class of compounds typically used as antidepressants in the treatment of depression, anxiety disorders, and some personality disorders.
The compounds belonging to the class of SSRIs are fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram and, recently introduced, its active enantiomer, escitalopram. Specific characteristic of this group of drugs is the different affinity for the serotonin transporter.

In this chart are reported the main SSRI drugs that work on the serotoninergic system:

Mechanism of action of antidepressive drugs

SSRIs are believed to inhibit the reuptake of serotonin from the synaptic cleft into the presynaptic cell, blocking the Na+ carrier. In this way serotonin can act longer on the post synaptic receptors, so its action is potentiated.
They have varying degrees of selectivity for the other monoamine transporters; for istance, they have only weak affinity for the noradrenaline and dopamine transporter.

The SSRIs may also inhibit the oxidative metabolism of drugs metabolised by isoenzymes of the hepatic microsomal cytochrome P-450 (2D6, 1A2, 3A4, etc..). The degree of inhibition is dose-dependent and varies from drug to drug; the most powerful drug to inhibit theCYP 2D6 was paroxetine, followed by fluoxetine.
*The paroxetine inhibits also the nitric oxyde synthase and the reuptake of the NA: it turned out to be the molecule with the greater anticholinergic action above all, through its action on the muscarinic receptors M3.
*The citalopram is the most selective between the SSRIs: it doesn’t interact with other carriers, it possesses a weak person affinity for the H-1 receivers of the histamine(neurochemical base of the light sedative effect), it doesn’t inhibit the activity of CYP 450 and, therefore, it doesn’t give place to dangerous interactions with other drugs.
*The sertralineis a dopamine reuptake inhibitor (blocks the carrier of DA) and this effect explains its disinhibiting properties and noticeable activators to cognitive level in the old patients, but it could carry to an excessive stimulation of the patient, with anxiety manifestations.

Despite of their common action, SSRIs are different in their chemical structure, metabolism and pharmacokinetics:
Comparative pharmacokinetics of selective serotonin reuptake inhibitors: a look behind the mirror. 1995

SSRI discontinuation syndrome

Definition SSRI discontinuation syndrome, also known as SSRI withdrawalsyndrome or SSRI cessation syndrome, is a syndrome that can occur followingthe discontinuation of the drug or a reduction in the dosage of the drug, even though the drug has not been completely discontinued. The time of onset of symptoms depends upon the elimination half-life of the drug and the patient's metabolism.

A key factor in the management of antidepressant discontinuation syndrome nowdays is the Prevention the clinician should inform the patient about the possibilities of side effects of using antidepressive drugs
[Antidepressant discontinuation syndrome--a problem for the clinician and the patient]. 2007

Discontinuation syndrome after SSRI antidepressants.2014

Symptoms come in two forms:
*usual: sweating, confusion, insomnia, nausea, vertigo, change of personality
*unusual: dizziness, electric shock-like sensations, nightmares and tremor.
They result from a global downregulation of serotonin receptors in response to increased levels of serotonin in the synaptic cleft, but the specific mechanism through which this creates symptoms is not understood.
Selective serotonin reuptake inhibitor antidepressant treatment discontinuation syndrome: a review of the clinical evidence and the possible mechanisms involved. 2013

What is withdrawal? It’s important to distinguish antidepressant withdrawal from any problem that might have led to treatment in the first instance. And it has some characteristics:
*If the problem begins immediately on reducing a dose, it is more likely to be a withdrawal problem.
*When original illnesses return, they take a long time to respond to treatment. A quick response to the reinstitution of treatment points to a withdrawal problem.
*Withdrawal may overlap with features of any problem for which you were first treated - both may contain elements of anxiety and of depression. Withdrawal will also often contain new features not in the original state including elements of anxiety and of depression like all other problems.
*If a treatment stops working and it’s needed more of the same drug, it has probably developed a dependence, so you may have withdrawal problems.

Treatment (how to withdraw?) there are different theories about dependence and withdrawal, so there are different approaches.

Enduring withdrawal We don’t know what causes enduring antidepressant withdrawal. It may be nothing to do with serotonin. Similar problems happen on antipsychotics and benzodiazepines, too.
In fact, benzodiazepines, another antidepressant class of drugs, are involved in a sort of withdrawal symptoms like SSRI, so there is no evidence of difference between their side effects.
Researchers also noticed that there are, actually, no differences between benzodiazepine and SSRI action.
What is the difference between dependence and withdrawal reactions? A comparison of benzodiazepines and selective serotonin re-uptake inhibitors.2012

SSRI withdrawal varies among individuals: may not be a problem for someone, while for others can last years. All the enduring problems can follow either abrupt or tapered discontinuation of treatment.
Also nowdays we don’t know how common these states are: many people presenting to their doctors are told they have a recurrent mood disorder and are put back on an antidepressant because the problems look “depressive”, and most doctors don’t think that problems of this sort could persist this long.

New frontieres Agomelatine is a new experimental drug compared to SSRI. Since now some clinical trials have been done, but there is no evidence of a significant clinical improvement. However, agomelatine revealed a lower rate of discontinuation due to side effects. Many other studies have to be done in order to define the importace and efficacy of this drug that is still in phase of experimentation.
Comparison of agomelatine and selective serotonin reuptake inhibitors/serotonin-norepinephrine reuptake inhibitors in major depressive disorder: A meta-analysis of head-to-head randomized clinical trials.2014

Marianna Francesca Pasquali
Beatrice Maria Trapani

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