Agentes Antidepresivos

Antidepressant Agents

Major depression is one of the most common psychiatric disorders. At any given moment, about 5– 6% of the population is depressed (point prevalence), and an estimated 10% of people may become depressed during their lives (lifetime prevalence).
Depression is a heterogeneous disorder that has been characterized and classified in a variety of ways.
Classification based onpresumed origin is as follows:
1) "reactive" or "secondary" depression (most common), occurring in response to real stimuli such as grief, illness, etc;
2) "endogenous" depression, a genetically determined biochemical disorder manifested by inability to experience ordinary pleasure or to cope with ordinary life events; and
3) depression associated with bipolar affective (manic-depressive)disorder.


The Pathogenesis of Major Depression
The Amine Hypothesis
Soon after the introduction of reserpine in the early 1950s, it became apparent that the drug could induce depression in patients being treated for hypertension and schizophrenia as well as in normal subjects. Within the next few years, pharmacologic studies revealed that the principal mechanism of action of reserpine was toinhibit the storage of amine neurotransmitters such as serotonin and norepinephrine in the vesicles of presynaptic nerve endings.
While the amine hypothesis is undoubtedly too simplistic, it has provided the major experimental models for the discovery of new antidepressant drugs. As a result, all the currently available antidepressant drugs—except bupropion—are classified as having their primaryactions on the metabolism, reuptake, or selective receptor antagonism of serotonin, norepinephrine, or both.
Neurotrophic Hypothesis
Cortisol levels elevated.
Basic Pharmacology of Antidepressants

Tricyclic Antidepressants (TCAs)
They closely resemble the phenothiazines chemically and, to a lesser extent, pharmacologically. Like the latter drugs, they were first thought to be useful asantihistamines with sedative properties and later as antipsychotics. The discovery of their antidepressant properties was a fortuitous clinical observation. Imipramine and amitriptyline are the prototypical drugs of the class as mixed norepinephrine and serotonin uptake inhibitors though they also have several other properties.

Heterocyclics; Second- and Third-Generation Drugs
Amoxapineandmaprotiline resemble the structure of the tricyclic agents, while trazodone and bupropion are distinctive. The heterocyclic agents are not notably different from the older agents in potency. Venlafaxine, a chemically unique third-generation agent; mirtazapine, an analog of a widely used European antidepressant; and nefazodone, developed on the basis of trazodone, have been introduced.

Since theintroduction of fluoxetine—an effective and more selective antidepressant with minimal autonomic toxicity—four more selective serotonin reuptake inhibitors have been introduced as well as the active enantiomeric form of one, (S)-citalopram. All are structurally distinct from the tricyclic molecules.

Monoamine Oxidase (MAO) Inhibitors
Phenelzine and isocarboxazid (no longer marketed); or nonhydrazides,which lack such a moiety, as with tranylcypromine. Tranylcypromine closely resembles dextroamphetamine, which is itself a weak inhibitor of MAO. Tranylcypromine retains some of the sympathomimetic characteristics of the amphetamines. The hydrazides appear to combine irreversibly with the enzyme, while tranylcypromine has a prolonged duration of effect even though it is not bound irreversibly.Pharmacokinetics

Tricyclics
Most tricyclics are incompletely absorbed and undergo significant first-pass metabolism. As a result of high protein binding and relatively high lipid solubility, volumes of distribution tend to be very large. Tricyclics are metabolized by two major routes: transformation of the tricyclic nucleus and alteration of the aliphatic side chain.

Heterocyclics
The...