Maprotiline dosing

Maprotiline, a tetracyclic drug, causes seizures at a higher incidence than do standard TCAs and is contraindicated in patients with a history of seizure disorder. The ceiling dose is considered to be 225 mg/day. 

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. 

MAPROTILINE HYDROCHLORIDE May be given as a single daily dose or in divided doses. Therapeutic effects are sometimes seen within 3 to 7 days, although as long as 2 to 3 weeks are usually necessary before improvement is observed. 

Mild to moderate depression An initial dose of 75 mg/day is suggested for outpatients. In some patients, especially the elderly, an initial dose of 25 mg/day may be used. Because of the long half-life of maprotiline, maintain initial dosage for 2 weeks. Gradually increase the dosage in 25 mg increments, as required and tolerated. Most patients respond to a dose of 150 mg/day, but doses as high as 225 mg/day may be required. 

Nortriptyline therapy should be initiated at 25 mg/day, and the dose should be increased to 75 mg/day over 1-2 weeks depending on tolerability and clinical response. Some patients require doses of up to 150 mg/day. Amoxapine therapy should be started at 50 mg/ day, and the dose should be titrated to 400 mg/day amoxapine has a short half-life and should be given in divided doses. Treatment with protriptyline can be started at 10 mg/day, and the dose can be increased to up to 60 mg/day. Maprotiline therapy should be started at 50 mg/day, and that dose should be maintained for 2 weeks the risk of seizure is increased if the dose is raised too quickly. The dose can be increased over 4 weeks to 225 mg/day. 

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. %... 

Maprotiline and bupropion cause more seizures than agents such as imipramine, amitriptyline, and nortriptyline. This issue, plus other safety concerns, has significantly limited the use of maprotiline. If maprotiline is used, many clinicians start with a low dose (75 mg per day or less in elderly patients), gradually increasing by 25-mg increments over 2 or more weeks (the drug has a half-life of about 48 hours). Average doses in outpatients are 150 mg, with a maximum of 225 mg. 

Amoxapine is also rapidly absorbed with protein binding of about 85%. The half-life is variable, and the drug is often given in divided doses. Amoxapine undergoes extensive hepatic metabolism. One of the active metabolites, 7-hydroxyamoxapine, is a potent D2 blocker and is associated with antipsychotic effects. Maprotiline is similarly well... 

An often troublesome adverse effect of antidepressant medication is weight gain. Two cases of this adverse effect have been reported in patients taking low doses of maprotiline (710). 

Maprotiline has relatively minor anticholinergic properties compared to amitriptyline. It has a very large elimination half-life of 36 to 48 h and in large doses produces convulsions. 

Maprotiline Similar to tricyclics seizures are dose-related... 

Maprotiline has a tetracyclic structure, in which the tricyclic nucleus adjoins a fourth ring formed by an ethylene bridge vertical to the major plane of the molecule (SEDA-5, 34). It has a strong inhibitory effect on noradrenaline uptake across cell membranes, and relatively weak effects on serotonergic mechanisms. The half-life averages 43 hours (1), allowing once-daily dosing. 

A 54-year-old man developed a stammer and speech blockage while taking maprotiline 75 mg/day (12). It responded to a reduction in dose to 50 mg/day, reappeared with another challenge of 75 mg/day, and did not respond to physostigmine intramuscularly on two occasions. It did not occur when he took desipramine 50 mg/day. 

Reports of overdose with maprotiline relate to doses of 750-3200 mg (21,22). The symptoms included impaired consciousness, convulsions, confusion, disorientation, visual hallucinations, and electrocardiographic changes similar to those seen with tricyclic compounds. Among 41 patients who had taken overdoses of maprotiline car-diotoxicity was equal to or greater than that of tricyclic drugs (23). Mania occurred in one case of maprotiline overdose (SEDA-17, 22). 

Disposition in the Body. Slowly but completely absorbed following oral administration. It appears to undergo significant first-pass metabolism bioavailability about 70%. After intravenous administration, about 57% of a dose is excreted in the urine and 30% in the faeces over a period of 21 days less than 10% of the dose is excreted as unchanged drug. The principal metabolite is the desmethyl derivative, which has been shown to be active in animals, but hydroxylation also occurs to form phenolic derivatives which may be further converted to aromatic methoxy ethers or excreted as glucuronide conjugates A -oxidation also occurs and maprotiline A -oxide has been reported to be active numerous minor metabolites have been identified in urine. 

Increased depressive effects when taken with other CNS depressants Cimetidine raises loflazepate plasma levels Rapid dose reduction or discontinuation of loflazepate during concomitant use with tetracyclic antidepressants such as maprotiline may result in convulsive seizures, possibly due to the loss of anticonvulsant actions that suppress the pro-convulsant actions of tetracyclic antidepressants... 

Risk of seizures increases with dose, especially with maprotiline above 200 mg/day... 

Maprotiline may precipitate seizures in toxic doses, as well as cardiotoxicity. 

Fluvoxamine inhibits the cytochrome P450 liver catabolic enzymes (predominantly this is inhibition of N-demethylation), leading to an increase in tricyclic antidepressant (TCA) serum levels. Plasma levels of several antidepressant drugs (e.g. amitriptyline, clomipramine, desipramine, imipramine, maprotiline, and nortriptyline) have been reported to increase by up to 4-fold during co-administration with fluvoxamine. Fluvoxamine at a daily dose of 50-100 mg causes a 3-4-fold increase in the plasma concentration of mirtazapine. 

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