ATC Group: N06A Antidepressants

Agomelatine is a melatonergic agonist (MT1 and MT2 receptors) and 5-HT2C antagonist. In humans, agomelatine has positive phase shifting properties; it induces a phase advance of sleep, body temperature decline and melatonin onset.

Amitriptyline is a tricyclic antidepressant and an analgesic. It prevents the re-uptake, and hence the inactivation of noradrenaline and serotonin at nerve terminals. Reuptake prevention of these monoamine neurotransmitters potentiate their action in the brain. This appears to be associated with the antidepressant activity.

Amoxapine is an antidepressant with a mild sedative component to its action. The mechanism of its clinical action in man is not well understood. Amoxapine is used in the treatment of major depressive disorder.

Bupropion is a selective inhibitor of the neuronal re-uptake of catecholamines (noradrenaline and dopamine) with minimal effect on the re-uptake of indolamines (serotonin) and does not inhibit either monoamine oxidase. The mechanism by which bupropion enhances the ability of patients to abstain from smoking is unknown. However, it is presumed that this action is mediated by noradrenergic and/or dopaminergic mechanisms.

Citalopram is the most Selective Serotonin Reuptake Inhibitor (SSRI) yet described, with no, or minimal, effect on noradrenaline (NA), dopamine (DA) and gamma aminobutyric acid (GABA) uptake.

The therapeutic activity of clomipramine is believed to be based on its ability to inhibit the neuronal re-uptake of noradrenaline (NA) and serotonin (5-HT) released in the synaptic cleft, with inhibition of 5-HT reuptake being the more important of these activities.

Desipramine is a tricyclic antidepressant. Desipramine is not a monoamine oxidase inhibitor (MAOI) and does not act primarily as a central nervous system stimulant. It has been found in some studies to have a more rapid onset of action than imipramine.

Dosulepin is a tricyclic antidepressant which acts by inhibiting the re-uptake of monoamine neurotransmitters into presynaptic neurone at central nervous system, so producing a clinical antidepressant effect. Dosulepin, in common with other tricyclics, inhibits the reuptake of noradrenaline and 5-hydroxytryptamine, with a significantly greater action on the uptake of noradrenaline.

Doxepin is not a central nervous system stimulant nor a monoamine oxidase inhibitor. The current hypothesis is that the clinical effects are due, at least in part, to influences on the adrenergic activity at the synapses so that deactivation of noradrenaline by reuptake into the nerve terminals is prevented.

Duloxetine is a combined serotonin (5-HT) and noradrenaline (NA) reuptake inhibitor. It weakly inhibits dopamine reuptake with no significant affinity for histaminergic, dopaminergic, cholinergic and adrenergic receptors.

Escitalopram is a selective inhibitor of serotonin (5-HT) re-uptake with high affinity for the primary binding site. It also binds to an allosteric site on the serotonin transporter, with a 1000 fold lower affinity.

Fluoxetine is a selective inhibitor of serotonin reuptake, and this probably accounts for the mechanism of action. Fluoxetine has practically no affinity to other receptors such as α₁, α₂, and β-adrenergic; serotonergic; dopaminergic; histaminergic₁; muscarinic; and GABA receptors.

The mechanism of action of fluvoxamine is thought to be related to selective serotonin re-uptake inhibition in brain neurones. There is minimum interference with noradrenergic processes. Receptor binding studies have demonstrated that fluvoxamine has negligible binding capacity to alpha adrenergic, beta adrenergic, histaminergic, muscarine cholinergic, dopaminergic or serotonergic receptors.

The mechanism of the antidepressant effect of gepirone is not fully understood but is thought to be related to its modulation of serotonergic activity in the CNS through selective agonist activity at 5HT1A receptors. The pharmacological activity of gepirone is attributed to the parent drug and its major metabolites 3'-OH-gepirone and 1-PP. Gepirone and its 3'-OH metabolite bind to 5HT1A receptors (Ki = 38 nM and 58 nM, respectively), where they act as agonists, while the 1-PP metabolite binds to alpha2 receptors (Ki = 42 nM).

Imipramine is a tricyclic antidepressant and has several pharmacological actions including alpha-adrenolytic, antihistamine, anticholinergic and 5HT-receptor blocking properties. However, the main therapeutic activity is believed to be inhibition of the neuronal re-uptake of noradrenaline and 5HT. Imipramine is a so-called “mixed” re-uptake blocker, i.e. it inhibits the reuptake of NA and 5HT to about the same extent.

Isocarboxazid is a monoamine oxidase inhibitor, effective in small doses. Its antidepressant action is thought to be related to its effect on physiological amines such as serotonin and noradrenaline, and this effect is cumulative and persistent.

Lofepramine is a tricyclic antidepressant. It exerts its therapeutic effect by blocking the uptake of noradrenaline by the nerve cell thus increasing the amine in the synaptic cleft and hence the effect on the receptors.

Maprotiline is a tetracyclic antidepressant, psychoanaleptics, non-selective mono-amine reuptake inhibitor, which shares a number of basic therapeutic properties with the tricyclic antidepressants. It displays a well-balanced spectrum of action, brightening mood and alleviating anxiety, agitation and psychomotor retardation. In masked depression, it can exert a favourable influence on somatic symptoms.

Melitracen is a tricyclic antidepressant with activating properties in low doses. It has similar pharmacological properties as amitriptyline but is less sedative.

Mianserin is a tetracyclic antidepressant. It does not appear to have significant anti-cholinergic properties, but has a marked sedative action. Unlike amitriptyline, it does not prevent the peripheral re-uptake of noradrenaline; it blocks presynaptic alpha-adrenoceptors and increases the turnover of brain noradrenaline.

Milnacipran is a selective serotonin and norepinephrine reuptake inhibitor (SNRI) indicated for the management of fibromyalgia in patients that are 18 years old or above.

Mirtazapine is a centrally active presynaptic α₂-antagonist, which increases central noradrenergic and serotonergic neurotransmission. The enhancement of serotonergic neurotransmission is specifically mediated via 5-HT₁ receptors, because 5-HT₂ and 5-HT₃ receptors are blocked by mirtazapine. Both enantiomers of mirtazapine are presumed to contribute to the antidepressant activity, the S(+) enantiomer by blocking α₂ and 5-HT₂ receptors and the R(-) enantiomer by blocking 5-HT₃ receptors.

Moclobemide is an antidepressant which affects the monoaminergic cerebral neurotransmitter system by means of a reversible inhibition of monoamine oxidase preferentially of type A (RIMA).

Nefazodone is a synthetically derived phenylpiperazine antidepressant. The mechanism of action of nefazodone, as with other antidepressants, is unknown. Preclinical studies have shown that nefazodone inhibits neuronal uptake of serotonin and norepinephrine.

Nortriptyline is a tricyclic antidepressant with actions and uses similar to these of amitriptyline. It is the principal active metabolite of amitriptyline.

Opipramol has high affinity for the sigma binding sites (type 1 and type 2) and has an antagonistic effect at the type 1 histamine receptors. The affinity for the type 2A serotonin receptors, type 2 dopamine receptors and the α-adrenergic receptors is lower. In contrast to the structurally related tricyclic antidepressants, opipramol has only slight anticholinergic activity and does not inhibit the reuptake of serotonin or noradrenaline. In humans, opipramol has sedating, anxiolytic and slight mood-elevating effects.

Paroxetine is a potent and selective inhibitor of 5-hydroxytryptamine (5-HT, serotonin) uptake and its antidepressant action and effectiveness in the treatment of OCD, Social Anxiety disorder/Social Phobia, General Anxiety Disorder, Post-Traumatic Stress Disorder and Panic Disorder is thought to be related to its specific inhibition of 5-HT uptake in brain neurones.

Phenelzine is an irreversible non-selective inhibitor of monoamine oxidase. Although the exact mechanism of action has not been determined, it appears that the irreversible, nonselective inhibition of MAO by phenelzine relieves depressive symptoms by causing an increase in the levels of serotonin, norepinephrine, and dopamine in the neuron. Phenelzine is used for the treatment of major depressive disorder. Has also been used with some success in the management of bulimia nervosa.

Reboxetine is a highly selective and potent inhibitor of noradrenaline reuptake. Noradrenaline reuptake inhibition and the consequent increase of noradrenaline availability in the synaptic cleft and modification of noradrenergic transmission, reportedly is among the most relevant mechanisms of action of known antidepressant drugs.

Sertraline is a potent and specific inhibitor of neuronal serotonin (5-HT) uptake in vitro, which results in the potentiation of the effects of 5-HT in animals. It has only very weak effects on norepinephrine and dopamine neuronal reuptake.

Tianeptine is an antidepressant. In man, tianeptine is characterised by marked action on somatic complaints, especially gastrointestinal complaints related to anxiety and mood disturbances. Moreover, tianeptine has no effect on sleep and alertness nor on the cholinergic system (no anticholinergic symptoms).

Trazodone is a potent antidepressant. It also has anxiety reducing activity. Trazodone is a triazolopyridine derivative chemically unrelated to known tricyclic, tetracyclic and other antidepressant agents. It has negligible effect on noradrenaline re-uptake mechanisms.

Venlafaxine has an antidepressant effect. The mechanism of its action in humans is believed to be associated with its potentiation of neurotransmitter activity in the central nervous system.

Vilazodone is a selective serotonin reuptake inhibitor and a 5HT_1A receptor partial agonist. It is used for the treatment of major depressive disorder (MDD) in adults. The mechanism of action of vilazodone in the treatment of major depressive disorder is not fully understood, but is thought to be related to its enhancement of serotonergic activity in the CNS through selective inhibition of serotonin reuptake.

Vortioxetine is a 5-HT₃, 5-HT₇, and 5-HT_1D receptor antagonist, 5-HT_1B receptor partial agonist, 5-HT_1A receptor agonist and inhibitor of the 5-HT transporter, leading to modulation of neurotransmission in several systems, including predominantly the serotonin but probably also the norepinephrine, dopamine, histamine, acetylcholine, GABA and glutamate systems. This multimodal activity is considered responsible for the antidepressant and anxiolytic-like effects and the improvement of cognitive function, learning and memory observed with vortioxetine in animal studies.