Maprotiline antidepressant

Lengthening the side chain produces the antidepressant maprotiline (73), which has a topological relationship to the clinically useful tricyclic antidepressants. The requisite acid is constructed by conjugate addition of the carbanion of anthrone (64) to acrylonitrile, followed by hydrolysis to give 70. Reduction of the carbonyl group with zinc and ammonia gives anthracene 71 by dehydration of the intermediate... 

GG is used extensively for analysis of antidepressants (Orsulak et al, 1989), but HPLC assays and enzyme immunoassays have become more popular in recent years. However, GC has advantages such as economy and ready availability. LCD and NPD generally are the detectors of choice (Coutts and Baker, 1982). NPD is relatively efficient for the analysis of tricyclic antidepressants (TCAs) as derivatization is not necessary, although the secondary, demethylated amines are sometimes derivatized to improve resolution and peak shape (Coutts and Baker, 1982). Acetylation, under aqueous or anhydrous conditions, followed by GC-NPD, has been used extensively for analysis of TCAs and the tetracyclic antidepressant maprotiline in plasma samples (Drebit et al., 1988). O Table 1-1 summarizes GC assays for some commonly prescribed antidepressants and their metabolites. 

Maprotiline and amoxapine are selective norepinephrine uptake inhibitors. They share most of the properties of the tricyclic antidepressants. Maprotiline has less sedating effect than mianserin and it is more epileptogenic than any other antidepressant. It shows considerable cardiotoxicity when taken in overdose. 

The hrst step in the preparation of the antidepressant maprotiline (33-5) takes advantage of the acidity of anthrone protons for incorporation of the side chain. Thus treatment of (30-1) with ethyl acrylate and a relatively mild base leads to the Michael adduct saponihcation of the ester group gives the corresponding acid (33-1). The ketone group is then reduced by means of zinc and ammonium hydroxide. Dehydration of the hrst-formed alcohol under acidic conditions leads to the formation of fully aromatic anthracene (33-2). Diels-Alder addition of ethylene under high pressure leads to the addition across the 9,10 positions and the formation of the central 2,2,2-bicyclooctyl moiety (33-3). The hnal steps involve the construction of the typical antidepressant side chain. The acid in (33-3) is thus converted to an acid chloride and that function reacted with methylamine to form the amide (33-4). Reduction to a secondary amine completes the synthesis of (33-5) [33]. 

The interaction between clonidine and the trieyelics is established and clinically important. The incidence is uncertain but it is not seen in all patients. Avoid concurrent use unless the effects can be monitored. Increasing the dosage of clonidine may possibly be effective. The clonidine dosage was apparently successfully titrated in 10 out of 11 hypertensive patients already on amitriptyline or imipramine. Only clomipramine, desipramine and imipramine have been implieated so far, but other tricyclics would be expected to behave similarly (amitriptyline, nortriptyline and protriptyline have been shown to interact in animals ). The tetracyclic antidepressants maprotiline and mianserin do not generally appear to interact with clonidine. The isolated case of hypotension with trazodone is of unknown general importance. 

Gundert-Remy U, Amann E, Hildebrandt R, Weber E. Lack of interaction between the tetracyclic antidepressant maprotiline and the centrally acting antihypertensive drug clcmidine. EurJClm Pharmacol (1983) 25,595-9. 

Doxepin [1668-19-5] (38), unlike other commercially available tricyclics, has an oxygen atom in the bridge between the two aromatic rings. It is marketed as a cis—trans mixture (1 5) of isomers, both of which are active. This close relative of amitriptyline (33) has both sedative and anxiolytic properties associated with its antidepressant profile. Maprotiline [10262-69-8] (39) and amoxapine [14028-44-5] (40) are pharmacologically, although not chemically, similar to the tricycHc secondary amines. Clomipramine [303-49-1] (41) has similar pharmacological and antidepressant efficacy. However, clomipramine is approved by the U.S. FDA only for the treatment of obsessive—compulsive disorder. Representative brands of tricycHc antidepressants marketed in the United States are Hsted in Table 2. 

Older tricyclic antidepressants are set in italics. The specificity of action of tricyclic antidepressants (in particular of amitritpyline, imipmmine, doxepine, noitriptyline, maprotiline) is limited because at therapeutic levels ihese drugs also block receptors (H t-histamine, a,-adrenergic, muscarinic). 

Rotzinger, S, Bourin, M, Akimoto, Y, Coutts, RT and Baker, GB (1999) Metabolism of some second and fourth generation antidepressants iprindole, viloxazine, buproprion, mianserin, maprotiline, trazodone, nefazodone and venlafaxine. Cell. Molec. Neurobiol. 19 427 42. 

The answer is c. (Hardman, p 436.) The tricyclics and second-generation antidepressants act by blocking serotonin or norepinephrine uptake into the presynaptic terminal. Fluoxetine selectively inhibits serotonin uptake with minimal effects on norepinephrine uptake. Protriptyline, maprotiline, desipramine, and amoxapine have greater effect on norepinephrine uptake... 

Pharmaceutical Comparison. At least 8 studies to date have examined the effectiveness of hypericum compared to the pharmaceutical antidepressants imipramine, amitriptyline, and maprotiline. Preliminary results indicate that hypericum is equivalent to standard antidepressants in effectiveness (Linde et al. 1996 Vorbach 1997). Similar to the pharmaceutical antidepressants, there is a 10-14 day lag for therapeutic effects of hypericum (Harrer et al. 1994). Indeed, the differences seen between hypericum and placebo groups becomes apparent between 2 and 4 weeks (Sommer and Harrer 1994). Hypericum has been reported to have a more favorable side-effect profile than several pharmaceutical antidepressants as well (Vorbach et al. 1994 Harrer et al. 1994). In double-blind studies, subjects have reported fewer and less-severe side effects. Although these initial results are promising, Linde and colleagues (1996) have concluded that the present evidence is inadequate to establish... 

In 1986, Baker et al. published an article describing the analysis of pentafluorobenzoyl and pentafluor-obenzenesulfonyl derivatives of several antidepressants and their metabolites (Baker et al., 1986c). The original article documented the derivatization of desipramine, 2-hydroxydesipramine, maprotiline,... 

The excellent clinical efficacy of the TCAs has been well documented and the pharmacokinetic profiles are favourable. The most serious disadvantage of the TCAs lies in their cardiotoxicity. Thus, with the exception of lofepramine, all the tricyclic antidepressants, including maprotiline, block the fast sodium channels in the heart which can lead to heart block and death. Approximately 15% of all patients with major depression die by suicide and a high proportion of these (up to 25%) do so by taking an overdose of TCAs. Such a dose can be as low as 5-10 times the recommended daily dose. 

Reboxetine is the only selective and reasonably potent noradrenaline reuptake inhibitor available clinically at the present time. Reboxetine has a chemical structure not dissimilar from viloxazine, an antidepressant which was of only limited clinical interest in the 1970s because of its weak efficacy and unacceptable side effects (nausea, vomiting and occasionally seizures). Unlike the secondary amine TCA antidepressants, such as maprotiline, desipramine, nortriptyline and protriptyline, reboxetine does not affect any other transporter or receptor system and therefore is largely devoid of TCA and SSRI-like side effects. In clinical trials, reboxetine has been shown to be as effective as the SSRIs in the... 

There are four classes of antidepressants tricyclic antidepressants (imipramine, trimipramine, amitriptyline, doxepin, desipramine, protriptyline, nortriptyline, amoxapine, maprotiline) monoaminooxidase (MAO) inhibitors (phenelzine, isocarboxazid, tranylcypromine) second-generation antidepressants or atypical antidepressants, which are a chemically dissimilar group of recently proposed drugs (bupropion, trazodone, fluoxetine) and amphetamines and other stimulators of the CNS (dextroamphetamine, methylphenidate). 

Maprotiline is frequently referred to as a tetracyclic antidepressant. This hybrid drug, containing both elements of classic tricyclic antidepressants and protriptyline elements, is pharmacologically and clinically more similar to imipramine. 

Maprotiline (Ludiomil) and amoxapine (Asendin) are heterocyclic antidepressant agents that are not members of the tricyclic family. However, their pharmacology is so similar to that of the tricyclic amines that they are included for discussion purposes with this class of agents. Desipramine and nortriptyline are major metabolites of imipramine and amitriptyline, respectively. 

Most child and adolescent studies published thus far have focused on the effects of the tricyclic antidepressants (TCAs) and, more recently, the SSRIs. A few open studies have also shown that monoamine oxidase inhibitors (MAOIs) can be used safely with children and adolescents (Ryan et ah, 1988b), but noncompliance with dietary requirements may present a significant problem for minors. Other antidepressants, including the heterocyclics (HTC) (e.g., amoxapine, maprotiline), buproprion, venlafaxine, and nefazodone, have been found to be efficacious for the treatment of depressed adults (APA, 2000), but they have not been well studied for the treatment of MDD in children and adolescents. Therefore, this chapter mainly describes the use of SSRIs and TCAs for youth with MDD. 

Reboxetine is a pure noradrenaline reuptake inhibitor that is licensed as an antidepressant in the United Kingdom. Reboxetine has established efficacy based on placebo-controlled studies both in the short and the long term. Previous noradrenaline reuptake inhibitors, such as desipramine, nortriptyline, and maprotiline, have been relatively selective for noradrenaline compared... 

Borsini F, Meli A Is the forced swimming test a suitable model for revealing antidepressant activity Psychopharmacology 94 147-160, 1988 Borsini F, Lecci A, Mancinelli A, et al Stimulation of dopamine D2 but not Dj receptors reduces immobility time of rats in the forced swimming test implication for antidepressant activity. Eur J Pharmacol 148 301-307, 1988 Bouchard JM, Delaunay J, Delisle J-P, et al Citalopram versus maprotiline a controlled clinical multicenter trial in depressed patients. Acta Psychiatr Scand 76 583-592, 1987... 

Results of crossover studies indicate that lithium is efficacious in treating acute depression in bipolar subjects unequivocally (36%, 29/80) and partially (43%. 34/80). respectively (Xomberg and Pope, 1993 Keck and McElroy, 2002). Various antidepressants have shown variable rates of efficacy in the treatment of acute bipolar depression, i.e. desipramine (50%), maprotiline (67%), imipra-mine (40 60%), tranylcypromine (87%), moclobemide (53%) and fluoxetine (60%) (Keck and McElroy, 2002). Among the anticonvulsants, valproic add and lamotrigine appear to have some potential efficacy in the treatment of acute bipolar depression (Calabrese et al., 1992, 1999 Fatemi et al., 1997). 

HCA is the term is used to refer to both TCAs and analogues of these agents, such as maprotiline and amoxapine. TCAs are by far the most commonly used HCAs and include tertiary amines such as amitriptyline, doxepin, and imipramine and secondary amines such as desipramine and nortriptyline. Most secondary amines could also be viewed as NE-selective antidepressants, while the hallmark of tertiary amine TCAs is their effects on multiple neurotransmitters over their clinically relevant dosing range. 

Two studies found maprotiline to be clearly superior to placebo and two other studies found trends in the same direction ( p < 0.001, combined data) (Table 7-5) (105, 106, 107 and 108). More than 1,600 patients were randomly assigned to either maprotiline or a standard HCA 660 on maprotiline did well, and 247 showed minimal improvement, no change, or worsened. For the HCAs (usually imipramine or amitriptyline), 640 patients did well, and 255 showed minimal improvement, no change, or worsened. In summary, 73% did well with maprotiline, and 72% did well with a standard antidepressant. Combining these data with the Mantel-Haenszel test indicated no difference in efficacy (Table 7-6). Maprotiline has a dose-dependent risk of seizures. As with TCAs and amoxapine, overdoses of maprotiline can be lethal. %... 

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