1/- The Depression :

1- Definition :

Depression is a decrease of neuropsychological tone, is a mood disorder, accompanied by a state of suffering psychic, it is expressed by :

  • The mood of sadness 4 The moral pain (loss of self-esteem)
  • L’inhibition psychomotrice (asthenia, difficulty concentrating)
  • The anxité
  • physical slowing (sleeping troubles, digestive disorders).
  • suicidal thoughts….

There are primary and secondary depression depression (Drug or organic origin)

2- Pathophysiology of depression :

A- The neurochemical theory :

This is the most accepted theory and involves biogenic amines, Depression is accompanied by a deficiency :

  • norepinephrine : giving vegetative and anxiety signs and psychomotor inhibition.
  • serotonin : involved in the regulation of mood.
  • Dopamine : c 'is the precursor of noradrenaline.

B- The neurohormonal theory :

(hypothalamic-pituitary axis) the basal level of cortisol is high.

C- New theories :

decreased brain levels of interleukins (EL-2 and IL-6), and prostaglandins (PG-E2).

2/- antidepressants :

1- Definition :

These are psychotropic substances that improve depressed mood in its most serious manifestations by acting on the entire existing depressive syndrome for at least 2 weeks.

On distingue :

  • the Antidepressants : stimulants depressed mood ; (covered in this course)
  • Les thymorégulateurs : mood stabilizers (lithium salt).

2- Classification :

a- chemical Classification : it is complex.

b- biochemical Classification : it classifies antidepressants according to their mechanism of action is based on single-aminergic systems.

  • Tricyclic antidepressants.
  • selective inhibitors of serotonin reuptake (ISRS)
  • Reuptake inhibitors of serotonin and NA (IRSN)
  • The iteurs inhibited MAO (HAD)
  • Action on autoreceptors ct2présynaptiques (mianserin).

3- The different classes of antidepressants :

a- Tricyclic antidepressants : Designated by this term because of their chemical stmcture. On distingue :

—> Tricyclic antidepressants imipramine where Imipramine (Tofranil®) is the prototype.

DCI tradename
Imipramine Tofranil®
Clomipramine Anafranil®
Amitriptyline Elavil®, Laroxyl®
desipramine Pertofran®
Dosulépine Prothiaden®
doxepin Quitaxon®, Sinéquan®
Tr imipramine Surmontil®

—> The related antidepressants (tétracvcliquesl :

Maprotiline (Ludiomil®) : this molecule has the same pharmacological properties of tricyclic.

1- Pharmacological action tricyclic ATD :

Mechanism & rsquo; Action : act by inhibiting the reuptake of biogenic amines (noradrenaline, serotonin) by presynaptic terminals.

According molecules antidepressant effect is dominated either by the sedative effect, or by an effect psychotonic. The choice is made depending on the patient's symptomatology.

On the central nervous system :

The tricyclic antidepressants have a sedative effect that can be beneficial in the beginning of treatment in a depressed that this sleep disorder.

The autonomic nervous system :

Tricyclic antidepressants have anticholinergic effect, adrenergic blocking high dose ; and an anti histamine Action.

On the cardiovascular system :

The most common effect is represented by postural hypotension.

Sinus tachycardia is due to inhibition of the reuptake of norepinephrine and the anticholinergic effect.

2- Pharmacokinetics tricyclic ATD :

The pharmacokinetics of imipramine is complex and highly variable from one molecule to another. Generally, still we can retain the following :

  • good absorption
  • Very high plasma protein binding (80-95%)
  • high volume of distribution (10-50 L / kg)
  • Metabolism by N-demethylation with the formation of active metabolites
  • Extended half-lives (often allowing once daily.
  • There placental transfer and in breast milk.

3- Indication : These are the depression of all kinds

Additional information:

  • Algies rebels : Amitriptyline, Imipramine
  • Preventing panic attacks : Clomipramine
  • pediatrics : behavioral disorders : Maprotiline, Imipramine The gradual increase in dosage is a rule to follow.

4- Adverse effects :

Adverse effects of imipramine are common, they are often benign..

On distingue :

  • The effects nenropsvchiaues : Anxious or delusional reactivations are possible, and a too rapid inversion of mood may lead to a manic state..
  • The effects anticholinergiaues : dry mouth ; epigastric pain ; constipation ; tachycardia ; vision trouble ; urinary retention.
  • Cardiovascular effects : L’hypotension orthostatique, arrhythmias and conduction disorders with risk of sudden death (related overdoses).
  • Endocrine effects : decreases in libido or defects erection during treatment, dysmenorrhea, hyperprolactinemia, weight gain are described.
  • Hematological disorders are exceptional. Allergic skin rash, of cholestatic hepatitis are possible.

5- Drugs interactions :

  • Drug interactions with other highly bound drugs (Aspirin, phenylbutazone, phenytoin).
  • Potentiation of the effects of tricyclic some oral contraceptives.
  • Barbiturates and many sedatives accelerate the hepatic metabolism of tricyclic.
  • Tricyclic potentiate the effects of alcohol and other sedatives.
  • The association is responsible for nonselective MAOI Serotonin syndrome .So The combination with non-selective MAO inhibitors is against-indicated, the rule is to respect an interval of 15 days after stopping MAOIs (Conversely, an interval of 5 days is enough to get tricyclic antidepressants with MAO).
  • Tricyclic and fluoxetine (ISRS) come into competition in metabolism which causes a rise in plasma concentration of tricyclic and can reach toxic threshold.

b- The ATD selective serotonin reuptake inhibitors (ISRS) :

They specifically and potently inhibit the reuptake of serotonin.

DCI tradename
Sertraline Zoloft®
fluoxetine Prozac ®
Fluvoxamine Floxyffal ®
paroxetine Deroxat ®
citalopram Séronam ®

They are much more developed because of a similar efficacy to tricyclic but have more clinical benefit :

  • They have no anticholinergic activity
  • They are devoid of cardiac toxicity
  • onset of action.

1- Indication :

These are the depression of all kinds. Their first-line use is easily justifiable in the elderly poly-medicated, suffering from cardiovascular disease and in patients with suicidal thoughts.

2- Side effects :

  • Digestive disorders (nausea, vomiting, anorexia)
  • Insomnia are described as well as headache and decreases libido.
  • withdrawal syndromes have been described.
  • Serotonin syndrome, often misunderstood, justifies immediate discontinuation of treatment. It is linked to certain overdoses or interactions and can result in hospitalization, even setting life-threatening. It combines a set of symptoms of digestive order (diarrhea), vegetative (sweats, thermal dysregulation, hypo ou hypertension), engines (tremors), neuropsychiques (confusion, agitation or coma).

3- Drugs interactions :

  • Association with the same selective MAO inhibitors ; et Clomipramine: serotonin syndrome.
  • Certains ISRS (ex : Fluvoxamine, paroxetine) are strong inhibitors. Therefore, risk of toxicity when using SSRIs and tricyclic antidepressants.
  • Half-life of & rsquo; elimination of very prolonged SSRI (up & rsquo; to 15 days for some d & rsquo; them), persistence in the & rsquo; body five to six weeks after arrest: l & rsquo; introduction & rsquo; an MAOI remains dangerous.
  • + Lithium: risk of confusion
  • + neuroleptic: troubles extrapyramidaux, heart rhythm disorders.
  • + Triptans: serotonin syndrome.
  • + carbamazepine : overdose (nausea, vomiting, visual disturbances, tremors, dizziness)
  • phenytoin : tremors, headaches, cognitive disorders
  • oral anticoagulants : sometimes bleeding (increased oversight needed)
  • diuretics : Many comments d & rsquo; hyponatremia, potentially serious (attention ++ in elderly)

c- The reuptake inhibitors of noradrenaline and serotonin : "Antidepressant dual action"

1- Venlafaxine (Effexor ): inhibits the reuptake of both serotonin and NA, their pharmacological effects similar to tricyclic but it carries fewer side effects.

Cons-indications : Association with non-selective MAO inhibitors or MAO-B inhibitors

You have to respect an interval of 15 days when switching from treatment with MAOIs and Venlafaxine and 7 days in case of reverse flow.

2- Milnacipran (Ixel®) : reuptake inhibitor of serotonin and NA. Indicated in major depressive disorder in adults.

Adverse effects ; dizziness, Heat and sweating access, digestive signs type (nausea and vomiting).Exceptionally, serotonin syndrome may occur, increased risk by association with MAOIs.

Cons-indications : Association with MAOIs.

d- Inhibitors of mono amine oxidase (HAD) :

There are two forms of MAO :

La MAO-A (responsible for the degradation of the amines mono-aminergic; noradrenaline , serotonin , and many dietary amines (ex. Tyramine).

La MAO-B (responsible for the conversion of certain toxic amines potentially involved in neurodegenerative processes)

Most MAOIs are no or very specific and inhibit 2 MAO but it is known that anti depressant effect is related to inhibition of MAO-A.

We distinguish 2 types of MAO used as antidepressants: non-selective MAO-A and MAO

1- The irreversible and non-selective MAO inhibitors :

They bind covalently MAO, the result is an irreversible inhibition and long-term (about several weeks) which lead to the destruction of the enzyme, we speak of "suicide inhibition".

The restoration of the MAO activity after a single dose of an irreversible MAOI requires 8 at 15 days.

On distingue :

iproniazid Marsilid®
Nialamide Niamide®

Their effectiveness is comparable to the reference tricyclic antidepressants but they are never offered as first-line because of their handling difficult. These products are reserved for depression resistant to treatment well led by tricyclic antidepressants; in fact they are hardly prescribed.

a- Side effects

  • antimuscarinic effects
  • Orthostatic hypotension
  • Insomnia
  • Access brutal hypertension if dietary intake of tyramine.
  • severe headache
  • cytolytic hepatitis (rares)
  • Suicide attempt, inversion of mood, delirium

b- Drugs interactions :

  • tricyclic antidepressants, ISRS, and NA reuptake inhibitors and 5-HT = serotonin syndrome
  • L-DOPA = potentiation of pharmacological effects
  • Reserpine = psychomotor agitation
  • sympathomimetic alpha, indirect sympathomimetic = hypertensive crises
  • Do not associate with foods rich in tyramine and tryptophan (Cheese)

2- The reversible inhibitors and selective MAO-A (HAD-A) :

MAO is not destroyed so that the lock is reversible and limited in time. On distingue :

Moclobemide C lamine®
Toloxatone Humoryl®

a- Side effects :

  • SNC : Insomnia, irritability, agitation (Moclobemide)
  • Digestive disorders
  • Dizziness, headaches
  • severe hepatitis (exceptional)
  • Lifting P psychomotor inhibition

b- drug interaction :

  • + Tricyclic antidepressant, hyperthermia, convulsion and coma.
  • The combination of levo-dopa and MAO inhibitors causes agitation and hypertension.
  • MAO inhibitors may interfere with the metabolism of other drugs. They extend and increase the effects of central depressants such as general anesthetics; sedatives ; l & rsquo; alcohol ; and antihistamines.

e- other antidepressants :

These antidepressants are of more recent onset and have features specific to each specialty. They do not show the toxicity of tricyclic (they often lack effects

Mechanism & rsquo; Action pharmacological effects


Receptor antagonist is 2 adrenergic ~ No effect or cardiotoxicity parasympatholytics.
~ It enhances the effects of alcohol and barbiturates.
Tianeptine (StabIon®) dopamine pathway Intermediate antidepressant effect
Viloxazine (Vivalan®) noradrenergic way No sedative effect

1- Side effects :

Rares : gastric (gastralgies, nausea, dry mouth) or neuropsychiatric. Some specific but serious reactions are known :

-mianserin : agranulocytose (should be withdrawn immediately and final treatment) – Tianeptine : hepatitis (requires immediate discontinuation)

2- Drugs interactions :

Tianeptine, mianserin : The combination with non-selective MAO = risk of serotonin syndrome.

Cours du Dr M.DOUAOUI. CHARBI – Faculty of Constantine