antidepressants
l MAO inhibitors (MAOI's)
l tricyclics & tetracyclics
l stimulants & Wellbutrin
l selective serotonin reuptake inhibitors (SSRI's)
l reboxetine
l other agents
Antidepressants work by altering the concentration of catecholamines and/or serotonin in CNS neurons emanating from the limbic system into the frontal lobe. Raising levels of catecholamines - excitatory, adrenalin-type neurotransmitters - causes stimulation. Elevating serotonin, an inhibitory neurotransmitter, produces a calming action, and results in subsequent upregulation of catecholamine systems as a mechanism of habituation.
MAO inhibitors (MAOI's)
The monoamine oxidase inhibitors (MAOI's) are the oldest class of antidepressants. They work by inhibiting MAO, an enzyme responsible for degradation of free catecholamine (adrenalin-type) neurotransmitters in neural synapses. This raises the level of excitatory neurotransmitter and lifts mood.
Phenelzine is one of the few MAOIs still marketed pharmaceutically. Selegiline (Eldepryl) and other MAOIs are used in Parkinsonism, a movement disorder resulting from dopamine deficiency or dysfunction. Selegiline, in doses less than about 30 mg/day, selectively inhibits MAO-B, the kind present in the CNS, without inhibiting the MAO-A present in the gut.
Hypericin is an MAOI which occurs naturally in St. John's wort. Those taking large amounts of OTC hypericin should be aware of the potential for antihypertensive crisis if dietary restrictions are not observed.
Moclobemide is a reversible inhibitor of MAO-A; when the compound de-binds, the enzyme is still active. It reportedly has a lower incidence of side effects than other MAOIs, including less drowsiness, dry mouth, blurred vision, and urinary retention.
The MAOIs are used only with reluctance due to their potentially fatal side effects. For years a clinical stand-by, Marplan was recently pulled from the market in the US because of insufficient sales. The main risk is hypertensive crisis ("the cheese reaction"). MAO is responsible for metabolizing indirect-acting sympathomimetics like tyramine which occur widely in foods and beverages. When MAO in the gut is inhibited, these amines accumulate in large quantities and displace adrenaline compounds from storage vesicles (like amphetamines, but peripherally), raising blood pressure dangerously.
The metabolism of MAOIs usually involves cleavage of the bonds to the amine (-NH-) group. This results in amphetamine compounds, but in much smaller amounts than typically taken for recreational purposes.
Another class of drugs in development inhibit catechol-O- methyltransferase (COMT), an enzyme which complements MAO in accomplishing catecholamine degradation.
Tricyclic antidepressants block reuptake pumps in monoamine nerve synapses. This extends the sojourn of neurotransmitters in the synapse and increases their concentration, affecting mood.
Although imipramine (Tofranil) is the prototype of the class, Elavil (amitriptyline) is probably the most well-known. Doxepin is also prescribed fairly often as a generic. Anafranil (clomipramine) is relatively selective for serotonin reuptake, although its desmethyl metabolite is much less so. (Metabolic reactions to active products are indicated by arrows with m's.)
Opipramol has been used as both an antidepressant and an antipsychotic; this implies some dopamine blocking action. Amineptine is a tricyclic dopamine reuptake inhibitor (same action as cocaine). Tianeptine, a similar compound, has been used as an antidepressant and stimulant and has anti-ulcerative and antiemetic effects.
Adrafinil is a stimulative alpha-agonist which (like the amphetamines) has been used in narcolepsy. Modafinil is a newer analog.
Tetracyclic compounds such as maprotiline follow the same pharmacologic paradigm as the tricyclics but may pose more problems in their elimination.
Drugs like amoxapine block serotonin (5-HT2) receptors as well as exhibiting a distinct dopamine blockade profile, i.e. they are not selective for D2. These are useful in cases where mania or psychosis are present. Dibenzepin and propizepine probably have similar actions.
The tricyclics have found application in other pathologies such as peripheral neuropathy and as analgesics for some kinds of chronic pain. However, they are relatively toxic in overdose, as they interfere with heart function and can cause cardiac arrest. They are highly lipophilic, bind to blood plasma proteins, and undergo fairly extensive metabolism. All these factors contribute to fairly long half-lives. Additionally, they have strong antimuscarinic side effects which limit compliance in patients. The typical symptoms of antimuscarinic drugs are dry mouth and constipation.
As with the MAOIs, the several adverse effects and risks of these drugs has led to the development of more selective agents such as the SSRIs (below) and a few novel tricyclics. More selective agents allow more selective manipulation of CNS activity.
Remeron (mirtazapine) stimulates release of norepinephrine and serotonin but simultaneously blocks serotonin at type 2 and 3 subreceptors. It closely resembles mianserin (Bolvidon), another serotonin antagonist. Remeron - and reportedly reboxetine - imparts much fewer sexual side effects than the SSRIs. The serotonin blocking component ay be important in some of the newer antipsychotic drugs.
tricyclics & tetracyclics
stimulants & Wellbutrin
Stimulants like Ritalin and dexedrine have been used historically as antidepressants, but because of their abuse potential and the availability of other agents they are seldom used for that purpose these days. Several analogs with profiles more suited to antidepressant therapy have been developed.
Wellbutrin enhances dopamine and norepinephrine function and has a stimulating profile, inducing seizure in high doses. Like the amphetamines, it may act as a dopamine releaser, but it is only a very mild reuptake inhibitor at noradrenergic and serotonin amine pumps. It could also act as a partial agonist at dopamine and/or norepinephrine terminals. Appending a bulky moiety like the tert-butyl group to a molecule which would otherwise be an agonist is a standard means of obtaining a partial agonist/ antagonist (see the narcotics page).
Wellbutrin (bupropion) is the only antidepressant without antisexual side effects (with the possible exception of reboxetine): most antidepressants inhibit orgasm. Coadministering Wellbutrin with other antidepressants (usually an SSRI; never an MAOI) reduces this antisexual effect.
Wellbutrin is currently being marketed as Zyban as an aid in smoking cessation. The rationale is to replace one dopamine-enhancing drug (nicotine) with another. The sustained-release form of this drug (Wellbutrin SR) is generally preferred since the half-life is relatively short.
Fenpentadiol resembles the threo diol of Wellbutrin, one of its active metabolites. Levophacetoperane (Lidepran) resembles methylphenidate (Ritalin).
olipram is a stimulant antidepressant synthesized in the 1970s which works, like caffeine, to inhibit the degradation of the second messenger cAMP by phosphodiesterase. There is renewed interest by some manufacturers along these lines. Rolicyprine is another pyrrolidione antidepressant.
Cotinine, a nicotine derivative, has been used as an antidepressant. (One man's poison is another man's antidepressant.) Methylxanthines (caffeine derivatives) like fencamine and dimethazan have also been used.
selective serotonin reuptake inhibitors (SSRI's)
The selective serotonin reuptake inhibitors (SSRI's) inhibit reuptake of serotonin without significantly affecting adrenergic systems. The adverse effect profiles are much less than the tricyclics, since muscarinic, histaminic and adrenergic binding is much reduced.
Zimeldine is a tricyclic analog that, like Anafranil, preferentially blocks serotonin reuptake. The newer agents, like Prozac, are structurally distinct from the tricyclics, and are called "atypical" agents.
Prozac is the most famous antidepressant. Lilly's sales of Prozac in 1993 exceeded 1 billion US dollars. Zoloft (sertraline), Paxil (paroxetine), Luvox (fluvoxamine), and Effexor (venlafaxine) are all available in the US. Effexor imparts significant catecholamine reuptake inhibition in addition too serotonin. Citalopram (Celexa) is another SSRI which is now very popular in Europe. Fluoxetine and femoxetine have also been tried in European weight-loss trials.
Trazodone (Desyrel) is an older SSRI that has often also been used as a sleeping aid. Its first metabolite, m-chloropiperazine, binds D2 better than thorazine (dopamine blocking action).
A newer variant is nefazodone (Serzone); it lacks the other notable, undesirable feature of trazodone, which is priapism in men (sustained erection, which in some cases is not reversible even by surgery). Serzone acts as an SSRI and also as a direct agonist at 5HT2 receptors.
Because serotonin is an inhibitory neurotransmitter, relief from anxiety is a beneficial side-effect. These drugs are also used to treat obsessive compulsive disorders, presumably by inhibiting repetitive firing in the mesocorticolimbic reward pathway.
The effect of these serotonin agents on mood has led to more complex theories of how antidepressants work. According to one hypothesis, the noradrenergic systems (dopamine, noradrenalin) which underlie the serotonin systems respond to an increase in the inhibitory serotonin function by upregulating, or increasing the number of receptors on the individual post-synaptic neural surface. This increase in adrenaline-type neural function might then account for the antidepressant activity which is delayed from the onset of serotonin reuptake inhibition by several weeks. Another possibility is that the serotonin receptors take a while to register the excess serotonin and resopond with similar mechanisms. In addition, recent evidence suggests interaction with DNA through transcriptases, increasing production of neurotransmitter by producing more synthase enzymes, for example.
The sexual side-effects of the SSRIs are mainly the inhibition ejaculation/orgasm although erectile dysfunction is also reported. This effect is putatively being ascribed to inhibition of nitrous oxide synthetase.
reboxetine
Reboxetine (Edronax) is a novel drug which selectively inhibits norepinephrine reuptake pumps. Such noradrenalin reuptake inhibitors (NARIs) represent an alternative to SSRIs.
other agents
Many other agents have been tried as antidepressants. Some of these are nutritive in nature, such as the deanol derivatives or phenylalanine. Others are analgesics (butacetin, nefopam) or sedative derivatives.
Other tricyclic structures that depart from the standard "6-7-6" ring structure of classic tricyclics have been used.
Other compounds like metralindole (a beta-carboline derivative) belong to novel structural classes with potentially distinct mechanisms of action.
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