Figure 12-26. Second-generation antidepressants. Trade names in parentheses. *Withdrawn in 1987.
It may be reasoned that if the acute effect of TCAs and MAO inhibitors is to raise the amine levels and yet no symptom relief is discernible for the first 2 weeks of treatment that the amine levels per se are not really significant; or that these compounds are achieving their results by a different technique—possibly a chronic effect, not necessarily involving only adrenergic neurons.
Effects on other receptors are known (e.g., antimuscarinic and antihistaminic), but these appear to elicit mostly side effects. The hypothesis that arises—and may replace the biogenic amine concept partially—is that it may be the chronic exposure of central p2-adrenoreceptors to these elevated biogenic amines (NE, 5-HT, and maybe DA also) that is the basis of the action. The most likely effect now seems to be decreased sensitivity of these receptors. By measuring c-AMP levels, studies using long-term drug administration indicate that central (J-receptors become less responsive postsynaptically and also that central 5-HT and di receptors may become enhanced.
With its 2-carbon bridge across the middle, maprotiline (Fig. 12-26) is technically a tetracyclic compound, yet it behaves as a secondary amine TCA (i.e., a relatively selective NE reuptake). The drug's second-generation standing is purely chronological. It has been in the U.S. market since 1981. Amoxapine, which was marketed the same year, is, of course, the N4-demethylated antipsychotic loxapine (Fig. 12-26). It has been suggested the cumulation of the 8-OH metabolite may be responsible for the inhibition of NE uptake and account for the antidepressant effect. Nomifensine, which is a tetrahydroisoquinoline with potential as an inhibitor of NE and DA, but not 5-HT, was withdrawn in 1987 for toxicity reasons.
Trazodone may be viewed as a triazolopyridine (left portion of the molecule) or as a phenylpiperazine. It is not to be easily categorized. It is inactive in most of the usual animal screens used. Its pharmacology is complex and not well understood. It shows weak serotonin uptake inhibiting ability and may also increase release of NE by blocking (*2-adrenoceptors. The major metabolite is m-chlorophenylpiperazine. Toxicities are low and some patients respond well; others obtain little benefit.
Six other atypical antidepressant drugs must be considered. Fluoxetine, which is the first of the selective serotonin reuptake inhibitors (SSRIs) was introduced (1986) as an antidepressant following extensive neurochemical research on the role of 5-HT in affective disorders as well as its relationship to NE and DA. The efficacy of this new addition to psychiatry is similar to the tricyclics; however, patient tolerance appears to be better due to a
different set of side effects. Thus, the TCAs, which typically produce sedation, considerable anticholinergic activity, and certain cardiovascular problems, can now be "traded" for occasional nausea, dizziness, and nervousness, a much more patient-acceptable profile. Both enatiomers are active.
Sertraline, which was introduced in 1992, has a similar mechanism, yet it may offer some advantage over fluoxetine by exhibiting little CNS action (i.e., it has less sedation and anxiety and is shorter acting). Both drugs show promise in the treatment of obesity and obsessive-compulsive behavior.
Three additional agents in this group were introduced in 1993-1994; paroxetine, ven-lafloxine, and fluvoxamin. They differ from the earlier agents in duration of action, dosages, and metabolism rather than in mechanism or clinical indications.
The modest improvements achieved in selectivity with respect to serotonin reuptake inhibition may also have been achieved with an isoenzyme system. Moclobemide, which was introduced in Sweden, reversibly inhibits monoamine oxidase A (RIMA). It is likely that this eliminates the severe hypertensive drug and food interactions that so severely limit the usefulness of the very effective earlier MAO inhibitors, since tyramine is now metabolized. An additional benefit of such agents may be a lack of cholinergic and cardiovascular effects.
Bupropion (Fig. 12-26) is a phenylethylamine resembling the anorexiant diethylpropion (Chapter 9). Since the iert-butyl group is not easily removed metabolically, the compound shows little or no pressor activity. That group and the keto function afford the compound lipid solubility, as does the meta-C 1 atom. It also probably protects it from facile oxidation of the phenyl ring. The compound is an atypical antidepressant, exhibiting some selectivity in DA reuptake (in rats). Some direct dopaminergic action on DA receptors seems also to exist. It shows no MAO inhibition. Dose-related CNS stimulation (in animals) has been reported. Because seizures have occurred at 450 mg daily doses, the drug is recommended to treat depression that is not responsive to other traditional antidepressants. It is not a first-choice drug.
Lithium. The discovery that Li+ can control manic behavior in manic-depressive patients was reported before the appearance of CPZ. It is now widely used as Li2C03. No totally acceptable mechanism for its action exists. Postulations involve actions that would likely adjust overactive catecholaminergic activity, which is the accepted occurrence in mania.
Several studies showing that Li+ has some antidepressant effects are known. Some weak biphasic alterations of NE and 5-HT turnover in the brain were established. Figure 12-27 is a simplified schematic model of a central dopaminergic neuron showing possible sites of drug action as discussed in this chapter and in Chapter 11. Similarly, Figure 12-28 depicts a noradrenergic neuron and its potential sites of drug action.
Stereochemical and other geometric factors are significant in determining the type of psychotropic activity obtained. It appears that planar ring systems yield optimal neuroleptic activity. The tricyclic 6-6-6 system (i.e., all three rings contain six atoms) of the phenoth-iazines seems to prove this. However, compounds with total rigid planarity, as in a 6-5-6 system exemplified by carbazole and fluorene derivatives, are invariably inactive. It might be postulated that neuroleptic receptors are planar but have rather strict size requirements for binding.
Ring systems with relatively few deviations from planarity, by angling of the atoms in the middle ring, begin to show some thymoleptic effects while still maintaining neuroleptic activity. Amitriptyline and doxepin are likely examples. More pronounced twisting of the ring system usually results in exclusive antidepressant action, such as with imipramine. A nonplanar angled thymoleptic receptor concept might be involved. Another supporting example may be the two acridine derivatives as shown here:
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