The physiopathology of depressive disorders, in spite of a lot of investigations, remains poorly understood. It is known however that certain drugs having noradrenergic or serotonergic impacts improve depressive states.

Antidepressants with exclusive serotonergic activity are studied in the chapter “Serotonin”.

Antidepressants with noradrenergic effects

Antidepressants with exclusive or predominant noradrenergic effects increase noradrenaline concentration in the synaptic clefts of the central nervous system by inhibiting its reuptake or by increasing its release. But the exact mechanism of their antidepressant effect is not known, because the biochemical effect is obtained quickly, whereas the improvement of mood occurs only after two or three weeks. This delay in onset of antidepressant effect supposes intervention of other directly or indirectly acting mechanisms.

The main inhibitors of noradrenaline reuptake are desipramine, quinupramine and viloxazine.

Desipramine and quinupramine have tricyclic chemical structure and anticholinergic effect. Viloxazine, which is not a tricyclic derivative, has a psychostimulant effect and it is advised to take it in the morning.

Trimipramine, a tricyclic derivative, inhibits noradrenaline reuptake but has also H1 antihistamine effect able to explain its sedative effect and anticholinergic effect.  It would have, in large doses, an atypical neuroleptic effect.

Mianserin increases noradrenaline concentration at the synaptic level, not by inhibition of its reuptake, but by increase of its release by inhibition of presynaptic alpha-2 receptors. It has moreover a H1 antihistamine effect which can explain its sedative effect. It has no anticholinergic effect.

Mirtazapine, a racemic, is also an adrenergic alpha-2 antagonist, having an antidepressant effect. It inhibits moreover 5HT2 and 5HT3 serotonin receptors and H1 histamine receptors, this last effect can explain its sedative action. A frequent adverse effect of mirtazapine is weight increase. It can also cause sometimes severe neutropenia.

Reboxetine is a selective inhibitor of noradrenaline reuptake, having an antidepressant effect, whose advantages compared to the products quoted previously remain to be specified. Although having little in vitro affinity for the muscarinic acetylcholine receptors, in patients it can give atropinic adverse effects.

Trimipramine SURMONTIL* Capsules

Antidepressants with noradrenergic and serotonergic effects

The antidepressants acting by inhibiting both serotonin and noradrenaline reuptake are imipramine, clomipramine, amitriptiline, doxepin, maprotiline and amoxapine.

Their activity results both from the drugs themselves and from their metabolites. Thus, clomipramine itself inhibits serotonin reuptake and its metabolite, desmethylclomipramine, inhibits that of noradrenaline.

Imipramine was the first molecule recognized as an antidepressant during a clinical trial not directed to this end. It was the Swiss psychiatrist Kuhn who detected its activity, whereas nothing suggested its existence. It is the leader of tricyclic antidepressants which are called imipraminic.

All the drugs previously quoted have tricyclic or tetracyclic (maprotiline) chemical structure and atropinic effects, amitriptyline having the strongest atropinic effect.

Atropinic effect, also called animuscarinic effect, is at the origin of disorders of accommodation with risk of glaucoma in patients with a closed angle and other disorders such as urinary retention, constipation and mouth dryness. Atropinic effect, especially in overdose, can also induce confusional and delirious states.

In overdose by voluntary or accidental poisoning, imipraminic derivatives induce life-threatening cardiac arrhythmia.

Amoxapine has, in addition to its inhibiting amines reuptake, 5HT2 antagonist effect and H1 antihistamine effect.

Milnacipran and venlafaxine are new non tricyclic inhibitors of the reuptake of noradrenaline and serotonin. Venlafaxine inhibits also dopamine reuptake and can induce a rise in diastolic arterial pressure as well as nervousness and anorexia. Its adverse effects are probably linked to its amphetaminic structure

Duloxetine is a new selective serotonin and norepinephrine reuptake inhibitor without significant effect on other mediators, used for the treatment of major depressive disorder and of neuropathic pain associated with diabetic peripheral neuropathy.

Nefazodone, a non tricyclic antidepressant, has, in addition to its inhibiting effect of noradrenaline and serotonin reuptake, a 5HT2 antagonist effect. It is metabolized by CYP3A4 which it inhibits and can induce various drug interactions.

Imipramine TOFRANIL* Tablets, Capsules
Amoxapine AMOXAPINE Tablets
Venlafaxine EFFEXOR* Tablets, Capsules

Antidepressants with dopaminergic effects

Many experimental and clinical data show that the stimulation of dopaminergic receptors elicits, at least in certain circumstances, antidepressant effect, vigilance stimulation and possibly addiction.

Amineptine inhibits dopamine reuptake and has antidepressant effect. It elicits insomnia and tachycardia and can cause addiction with self-increased intake of high doses. In addition, amineptine can elicit hepatitis. Because of its adverse effects, amineptine was withdrawn from the market.

Tianeptine, chemically close to amineptine, has also an antidepressant effect without inhibiting dopamine reuptake. However it has dopaminomimetic effects whose mechanisms are not well known.

Bupropion, also called amfebutamone, initially used as antidepressant is now used in a sustained-release formulation as an aid to stopping smoking. Its chemical structure is of amphetaminic type, quite similar to that of diethylpropion, also called amfepramone, which has been used for a long time as an anorexiant.

Bupropion inhibits dopamine, noradrenaline and serotonin reuptake.

Bupropion WELLBUTRIN*Tablets, SR, XL
ZYBAN* SR Tablets

Its most frequent adverse effects are insomnia, anxiety, dry mouth, nausea. It can facilitate seizures and is contra-indicated in patients with epilepsy. Bupropion does not induce sexual disorders contrary to most other antidepressants; it could improve them.  In case of overdose, seizures, hallucinations, nausea or vomiting, tachycardia can be observed.

Antidepressants with MAOI activity

MAOI inhibit the catabolism of monoamines, noradrenaline, dopamine and serotonin and increase their concentration in the synaptic cleft. According to their predominant effect on each of these amines, MAOI have antidepressant or antiparkinsonian effects. The antidepressants are iproniazid and moclobemide. They are studied in the chapter “Serotonin”

MAOIs which increase the dopamine concentration preferentially are used as antiparkinsonian (see below).
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