Major depressive disorder (MDD), 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 MDD are of varied chemical structures; many have effects that enhance the CNS actions of norepinephrine, serotonin, or both.
THE AMINE HYPOTHESIS OF MOOD
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 of patients do not reveal decreases in the brain levels of NE or 5-HT; (2) although antidepressant drugs may cause changes in brain amine activity within hours, clinical response requires weeks; (3) most antidepressants ultimately cause a downregulation of amine receptors; (4) bupropion has minimal effects on brain NE or 5-HT; (5) brain-derived neurotrophic factor (BDNF) is depressed in the brains of depressed patients; (6) chronic use of antidepressants reduces glutamatergic transmission and ketamine, a potent NMDA antagonist, has a notable, rapid, antidepressant action.
DRUG CLASSIFICATION & PHARMACOKINETICS
A. 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.
B. Selective Serotonin Reuptake Inhibitors
Fluoxetine is the prototype of a group of drugs that are selective serotonin reuptake inhibitors (SSRIs). All of them require hepatic metabolism and have half-lives of 18–24 h. However, fluoxetine forms an active metabolite with a half-life of several days (the basis for a once-weekly formulation). Other members of this group (eg, citalopram, escitalopram, fluvoxamine, paroxetine, and sertraline) do not form long-acting metabolites.
High-Yield Terms to Learn
|Amine hypothesis of mood ||The 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 ...|