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Major depressive disorder, or endogenous depression, is a depression of mood without any obvious medical or situational causes, manifested by an inability to cope with ordinary events or experience pleasure. The drugs used in major depressive disorder are of varied chemical structures; many have effects that enhance the CNS actions of norepinephrine, serotonin, or both.


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Amine hypothesis of moodThe hypothesis that major depressive disorders result from a functional deficiency of norepinephrine or serotonin at synapses in the CNS
MAO inhibitors (MAOIs)Drugs inhibiting monoamine oxidases that metabolize norepinephrine and serotonin MAO type A) and dopamine (MAO type B)
Tricyclic antidepressants (TCAs)Structurally related drugs that block reuptake transporters of both norepinephrine (NE) and serotonin (5-HT)
Selective serotonin reuptake inhibitors (SSRIs)Drugs that selectively inhibit serotonin (5-HT) transporters with only modest effects on other neurotransmitters
Serotonin-norepinephrine reuptake inhibitors (SNRIs)Heterocyclic drugs that block NE and 5-HT transporters, but lack the alpha blocking, anticholinergic and antihistaminic actions of TCAs
5-HT2 receptor antagonistsStructurally related drugs that block this subgroup of serotonin receptors with only minor effects on amine transporters
HeterocyclicsTerm used for antidepressants of varying chemical structures, the characteristics of which do not strictly conform to any of the above designations

The amine hypothesis of mood postulates that brain amines, particularly norepinephrine (NE) and serotonin (5-HT), are neurotransmitters in pathways that function in the expression of mood. According to the hypothesis, a functional decrease in the activity of such amines is thought to result in depression; a functional increase of activity results in mood elevation. The amine hypothesis is largely based on studies showing that many drugs capable of alleviating symptoms of major depressive disorders enhance the actions of the central nervous system (CNS) neurotransmitters 5-HT and NE. Difficulties with this hypothesis include the facts that (1) postmortem studies do not reveal any decreases in the brain levels of NE or 5-HT in patients suffering from depression; (2) although antidepressant drugs may cause changes in brain amine activity within hours, weeks may be required for them to achieve clinical effects; (3) most antidepressants ultimately cause a downregulation of amine receptors; and (4) at least 1 effective antidepressant, bupropion, has minimal effects on brain NE or 5-HT.

Tricyclic Antidepressants

Tricyclic antidepressants (TCAs; eg, imipramine, amitriptyline) are structurally related to the phenothiazine antipsychotics and share certain of their pharmacologic effects. The TCAs are well absorbed orally but may undergo first-pass metabolism. They have high volumes of distribution and are not readily dialyzable. Extensive hepatic metabolism is required before their elimination; plasma half-lives of 8–36 h usually permit once-daily dosing. Both amitriptyline and imipramine form active metabolites, nortriptyline and desipramine, respectively.

Selective Serotonin Reuptake Inhibitors

Fluoxetine is the prototype of a group of drugs that are selective serotonin reuptake inhibitors (SSRIs). ...

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