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Robert Maurer

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See also: Symptoms of Depression - Antidepressants, Depression Drugs


Antidepressants are a highly studied and widely used class of drugs to treat mood disorders, such as depression and bipolar disorder.
In fact, nowadays, these drugs are also used in the treatment of neuropathic pain, obsessive-compulsive disorders and in therapy for smoking cessation.
To understand how antidepressants were developed, and to better understand the meaning of their mechanism of action, it is useful to know what depression is and what its possible causes are.

What is Depression

Depression is a very common and well-known psychiatric disease. During the depressive state, patients feel hopeless and experience a sense of uselessness, helplessness and hopelessness.
The depressive state does not only involve the patient's mood and mind, but also affects the body, alters eating habits, sleep, self-perception, affective manifestations and the behavior of an individual.
Depression is among the five most common diseases in the Western world and affects 12% of the population. The incidence of this pathology in men and women is 1: 2.
Depression can also develop in children and adolescents, with an incidence of one in every 50 children under the age of 12 and one in every 20 adolescents.
In particular, adolescent depression mainly affects girls, probably due to the hormonal and body changes that occur in puberty.
Premenstrual depressive syndrome (PMS) and post-partum depression represent other depressive states of the female sphere in which the cause of the disease can be attributed to the variation of hormones.
Depression, however, also affects the elderly. In this category of patients, the symptoms associated with depressive pathology are often attributed to a normal aging condition; this can lead to misdiagnosis, leading to worsening of the disease. Also, very often older people are reluctant to express feelings of sadness or hopelessness, which makes diagnosing depression even more difficult.
In any case, whatever the cause of the depression and the category of patients it affects, it is necessary to intervene as soon as possible with an accurate diagnosis and an appropriate pharmacological treatment to avoid the chronicization of the disease.
There are many types of depression, which can be differentiated according to the type and severity of symptoms and according to the age of onset.
Some of the best known depressive pathologies are briefly discussed below.

Unipolar depression or major depression (MDD)

This form of depression is the most serious of the various types of depressive pathologies. It occurs with symptoms that prevent you from carrying out normal activities - such as working, studying, eating, sleeping - and preventing you from carrying out leisure activities.
Major depression appears to have family predispositions and appears to be hereditary.
Treatment is generally pharmacological and accompanied by psychotherapy. In very severe cases, electroconvulsive therapy (otherwise called electroshock) could also be used.


Dysthymia is a mood disorder with symptoms very similar to those of depression. These symptoms are milder but tend to last for long periods (usually two years or more for adults and one year for children and adolescents).
The treatment of this disorder is pharmacological and psychotherapeutic.

Bipolar disorders (manic-depressive disorders)

Bipolar disorders are characterized by an alternation of depressive states and manic or hypomanic states.
These psychiatric disorders are divided into:

  • Bipolar I Disorder (characterized by manic-depressive episodes);
  • Bipolar II disorder (characterized by hypomaniac-depressive episodes);
  • Cyclothymic disorder o cyclothymia (a disorder whose minimum duration is two years and is characterized by hypomaniac-depressive episodes).

The drug treatment of this type of disorder involves the use of mood stabilizers (such as, for example, lithium) or a combination of antidepressant and antipsychotic drugs.

Causes of Depression

To date, it is believed that the cause of depression is attributable to the role played by certain types of neurotransmitters. These neurotransmitters are monoamines Serotonin (o 5-HT), norepinephrine (o NA) is dopamine (o DA).
To better understand the mechanism of action of these neurotransmitters, a brief introduction to their physiology is essential.
Serotonin, noradrenaline and dopamine are synthesized within monoaminergic neurons. In particular, 5-HT is synthesized in serotonergic neurons, NA in noradrenergic neurons and DA in dopaminergic neurons.
Once synthesized, monoamines are stored in vesicles and released into the synaptic wall (the space between the presynaptic and postsynaptic nerve terminals) in response to certain stimuli.
Once released into the synaptic space, the monoamines interact with their own receptors located both on the membrane of the postsynaptic nerve terminal and on the membrane of the presynaptic nerve terminal. This interaction gives rise to a cascade of signals that leads to a certain biological response.
After carrying out their function, monoamines bind to the receptors responsible for their reuptake (SERT for serotonin reuptake e NET for noradrenaline reuptake) and are returned to the presynaptic nerve end.
Once recaptured, monoamines are metabolized by specific enzymes, monoamine oxidase (MAO) and catechol-O-methyl transferasi (COMT).

In fact, the exact cause of depression isn't well known. In this regard, various hypotheses have been formulated:

Monoaminergic hypothesis

According to this hypothesis, depression is caused by a deficiency of serotonin, noradrenaline and dopamine.
Supporting this theory is the fact that antidepressant drugs increase the transmission of these monoamines.
However, antidepressants alter monoamine concentrations very rapidly, but the therapeutic effect only sets in after weeks. Furthermore, there is no relationship between the potency of the effect on the extracellular concentration of monoamines and the antidepressant efficacy; in other words, a drug capable of greatly increasing the concentration of monoamines in the synaptic wall does not necessarily have better antidepressant properties.
Therefore, it is clear that serotonin, noradrenaline and dopamine deficiency cannot be the only trigger for depression.

Hypothesis of receptor sensitivity

This hypothesis states that depression is caused not simply by a deficiency of monoamines, but also by an altered sensitivity of the postsynaptic receptors towards these same neurotransmitters.
The concept behind this theory is that in patients with depression, the serotonergic and noradrenergic postsynaptic receptors have become hypersensitive to their respective neurotransmitters as a result of their depletion from the synaptic wall.
The antidepressant drugs, therefore, would induce a hyposensitivity of these same receptors and this would explain why the therapeutic effect is established only after a few weeks from the beginning of the treatment.

Permissive hypothesis

This hypothesis highlights the importance of the mutual balance of serotonin and noradrenaline in the mood-regulating processes.
In fact, if the serotonin level is too low, noradrenergic regulation is lost and this can generate alterations in noradrenaline levels. Such alterations can lead to mania.
If, on the other hand, it is the norepinephrine level that falls, serotonergic regulation is lost with consequent alteration of serotonin levels. This leads to the onset of symptoms typical of depression.

Hormonal hypothesis

This hypothesis states that the alteration of the hypothalamic-pituitary-adrenal axis (HPA) may be able to affect the levels of serotonin and noradrenaline released by the respective neurons, thus compromising their functioning.

The various hypotheses formulated, therefore, all agree in affirming that depression is due - directly or indirectly - to alterations in the levels of serotonin and noradrenaline. As for dopamine, although its role in the etiology of depression is still unclear, it is still believed to be involved in the onset of the disease.
Although the monoaminergic hypothesis is insufficient to explain why depression develops, it still remains the most accredited hypothesis. The monoaminergic therapeutic approach is the most successful and, in fact, most antidepressant drugs act by increasing serotonergic and noradrenergic transmission.

Development of antidepressant drugs

Before 1950 there were no antidepressant drugs as we understand them today. The only therapies used in the treatment of depression centered on the use of amphetamine stimulants or electroconvulsive therapy. However, the use of amphetamine drugs was often ineffective, resulting in an increase in the patient's activity and energy. Electroconvulsive therapy, on the other hand - although effective - terrified patients because it caused pain.
The first antidepressant drugs were discovered in the late 50s. Those drugs were the tricyclic antidepressants (TCA) he monoamine oxidase inhibitors (HAD).
As with many of the most important discoveries made by man, the synthesis of antidepressants did not arise from design but from chance.
The progenitor of tricyclic antidepressants - theimipramina - was discovered by the Swiss psychiatrist Ronald Kuhn while he was looking for new compounds similar to chlorpromazine for the treatment of schizophrenia.
The second major discovery was that of monoamine oxidase inhibitors. Also this time, the discovery came by chance thanks to the development of analogues of isoniazid (hydrazide of nicotinic acid), a drug used in the treatment of tuberculosis.
The first analogue of isoniazid to be synthesized was theiproniazid. During the clinical trial phases of this derivative, a considerable improvement in mood was noted in patients suffering from tuberculosis. However, Iproniazide was found to be hepatotoxic at the therapeutic doses necessary to obtain both an antituberculous and an antidepressant action.
The discovery of the antidepressant action of iproniazide, however, gave impetus to the search for new inhibitors of monoamine oxidase. This impulse led to the synthesis of hydrazine derivatives and non-hydrazine derivatives with lower toxicity than that induced by hyproniazide.
However, due to the side effects that the first TCAs and MAOIs induced - especially at the cardiovascular level - it was necessary to search for new drugs capable of increasing the monoaminergic signal without inducing such serious adverse effects.
In the late 60s it was discovered that some antihistamine drugs were able to selectively inhibit serotonin reuptake and were devoid of cardiotoxicity.
Since, with the use of TCAs and MAOIs, the importance of serotonin in depressive pathologies was immediately clear, the aim of pharmaceutical chemists was to identify and synthesize drugs selective serotonin reuptake inhibitors (SSRI), with the aim of obtaining highly selective compounds for the serotonin reuptake transporter, but with fewer side effects - or at least with less serious side effects - than those induced by TCA and MAOI.
The first success in this area was achieved with the synthesis of the zimeldina, a derivative of amitriptyline (a TCA). This molecule, in fact, was able to selectively inhibit the reuptake of 5-HT with a minimal effect on the reuptake of noradrenaline and did not have the typical side effects of TCAs. Zimeldine was then withdrawn in the early 80s as it favored the development of Guillain-Barré syndrome.
In any case, the success achieved with zimeldine gave the impetus for the development of new antidepressant drugs. This impulse led - in the late 70s - to the discovery of many new SSRIs and other antidepressant drugs, such as norepinephrine and serotonin reuptake inhibitors (NSRIs).

Classes of antidepressant drugs

As mentioned above, the development of antidepressant drugs had a significant boost in the late 70s and throughout the 80s. This led to the synthesis of new and numerous molecules.
Below are the main classes of antidepressant drugs still used today.

Tricyclic antidepressants (TCAs)

As stated above, these drugs were the first real antidepressants to be discovered.

TCAs inhibit the reuptake of both serotonin and norepinephrine by binding to the receptors responsible for their reuptake within the presynaptic nerve termination, the SERT and the NET.
However, these drugs cause many side effects, as they also inhibit other systems in the body. For this reason, TCAs are referred to as "dirty drugs".
In particular, TCAs are able to:

  • Block muscarinic receptors (anticholinergic action);
  • Block α1-adrenergic receptors;
  • Block H1 receptors (antihistamine action);
  • Block sodium channels in the heart and central nervous system.

Theamitriptilina, L 'imipramina clomipramine nortriptilina desipramina el 'amoxapine.

Selective Serotonin Reuptake Inhibitors (SSRIs)

SSRIs selectively bind to SERT, thereby inhibiting serotonin reuptake. Unlike TCAs, they do not block muscarinic, adrenergic and serotonergic receptors and, above all, they are not cardiotoxic.
They belong to this class of drugs fluoxetine fluvoxamine, citalopram, L 'escitalopram sertraline and paroxetine.

Norepinephrine and serotonin reuptake inhibitors (NSRIs)

As the name implies, these drugs inhibit the reuptake of both serotonin and norepinephrine by binding to SERT and NET receptors.
In a sense, TCAs can be considered the precursors of this class of antidepressants.
However, NSRIs - unlike their tricyclic precursors - do not block other neuroreceptors and, therefore, have fewer side effects.
They belong to this class of drugs duloxetine and venlafaxine.

Selective norepinephrine reuptake inhibitors (NaRIs)

The selective norepinephrine reuptake inhibitors selectively bind to the NET receptor, thus favoring a longer stay of the neurotransmitter in the synaptic wall.
The reboxetina.

Serotonergic Transmission Modulators (SARI)

The drugs belonging to this class exert their antidepressant action by enhancing the serotonergic transmission through the antagonism towards the 5-HT2 receptors and through a weak inhibition of the reuptake of the same neurotransmitter.
The trazodone and nefazodone.

Modulators of noradrenergic and serotonergic transmission (NaSSA)

This category of drugs performs its antidepressant action by antagonizing the α2 adrenergic receptors and antagonizing the 5-HT2 or 5-HT3 serotonin receptors.
It belongs to this class of drugs mirtazapina.

Dopamine and norepinephrine reuptake inhibitors (DNRIs)

These drugs selectively inhibit dopamine and - to a lesser extent - norepinephrine reuptake. They can also exert mild inhibition of serotonin reuptake.
The bupropione, a drug used - as well as in the treatment of major depression - also in the therapy for smoking cessation.

Monoamine oxidase inhibitors (MAOIs)

As their name implies, these drugs work by inhibiting particular types of enzymes, called monoamine oxidase and responsible for the metabolism of monoamines.
Two isoforms of MAOs are known, MAO-A and MAO-B.
The drugs used in the treatment of depression are non-selective MAO inhibitors - such as fenelzina e tranilcipromina - and selective MAO-A inhibitors, such as moclobemide.
Selective MAO-B inhibitors are, on the other hand, used above all in the treatment of Parkinson's disease.

Mood stabilizers

Mood stabilizers are used to treat bipolar disorder. They can have both acute and long-term effects.
The best known mood stabilizer is definitely the lithium carbonate.

Herbal therapy

Herbal therapy can also be used to treat mild to moderate depression. In particular, it refers to the treatment of depressive pathology withhypericum, otherwise known as St. John's wort.
This plant, in fact, is able to inhibit the reuptake of serotonin exactly like SSRIs, but, moreover, it is able to increase the levels of noradrenaline, with a consequent increase in energy and responsiveness. Finally, hypericum is also capable of increasing dopamine levels, thus promoting an increased sense of well-being.

Other articles on 'Antidepressants'

  1. Antidepressants, drugs for depression
  2. Symptoms Depression
  3. Depressive disorders: major depressive episode
  4. Major depressive episode symptoms
  5. Dysthymic disorder
  6. Mania and manic episode
  7. Bipolar disorder
  8. Depression - Medicines to Treat Depression
  9. Depression and St. John's wort
Audio Video Antidepressants
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