Maprotiline


Maprotiline, sold under the brand name Ludiomil among others, is a tetracyclic antidepressant that is used in the treatment of depression. It may alternatively be classified as a tricyclic antidepressant, specifically a secondary amine. In terms of its chemistry and pharmacology, maprotiline is closely related to such-other secondary-amine TCAs as nortriptyline and protriptyline and has similar effects to them, albeit with more distinct anxiolytic effects. Additionally, whereas protriptyline tends to be somewhat more stimulating and in any case is distinctly more-or-less non-sedating, mild degrees of sedation may be experienced with maprotiline.

Medical uses

Maprotiline is used in the treatment of depression, such as depression associated with agitation or anxiety and has similar efficacy to the antidepressant drug moclobemide. This finding has also been validated by a group of general practitioners who compared the respective efficacy and tolerability of maprotiline and moclobemide.
The use of maprotiline in the treatment of enuresis in pediatric patients has so far not been systematically explored and its use is not recommended. Safety and effectiveness in the pediatric population in general have not been established. Anyone considering the use of maprotiline in a child or adolescent must balance the potential risks with the clinical need.
A very small body of research has also explored the potential of maprotiline in treating diabetic kidney disease and it has been measured against amitriptyline in this regard.
Maprotiline and fluoxetine have also been found, among certain lines of research, to have quite potent anti-profilerative effects against certain forms of cancer of the Burkitt lymphoma type. One study also bore ought a certain level of evidence regarding maprotiline’s ability to suppress both cholesterol biosynthesis and hepatocellular carcinoma liver-cancer progression.
Maprotiline was also measured against imipramine, fluoxetine and ketamine in an experiment-model involving two different kinds of chicken differently-conditioned against stress, including Australorps in the proposed treatment of treatment-resistant depression in humans.
In general, lower dosages are recommended for patients over 60 years of age. Dosages of 50 mg to 75 mg daily are usually satisfactory as maintenance therapy for elderly patients who do not tolerate higher amounts. In any case, 225 m.g./d. is the absolute-maximum highest recommended dose for this drug, as any more can predispose more significantly to seizures. 150 m.g. is the average optimal daily dose for otherwise-healthy patients who can tolerate a full dose.

Available forms

  • Coated tablets: 10 mg, 25 mg, 50 mg, and 75 mg
  • Injectable concentrate, 25 mg

    Contraindications

In generalised theory, maprotiline may somewhat worsen certain features of schizophrenia, necessitating caution in prescribing them to someone with it and continuation of the antipsychotic treatment. However, certain bodies of evidence have found maprotiline a useful augment in treating some of the negative, or "anaesthetic", symptoms of schizophrenia and in probable extension pronounced schizoidia. It has also been weighed against fluvoxamine in this overall regard, with fluvoxamine evidencing clear superiority therein. Maprotiline, however, may be specifically useful for the "negative symptom" of alogia and in this regard was found demonstrably superior to the other control-drugs in one study. Citalopram, clomipramine and fluvoxamine appeared particularly useful in the study for reducing affective blunting, with alprazolam and maprotiline ranking joint-next.
Patients with bipolar affective disorder should not receive antidepressants whilst in a manic phase under any circumstances whatsoever. This is because antidepressants are known to come with the risk of worsening acute mania or precipitating it in so vulnerably-predisposed people.
They may also negatively interfere with the treatment of mixed bipolar states, where electro-convulsive therapy, valproate and antipsychotics prove more beneficial. However, maprotiline was put to good use in one particular case, of one young man presenting with what was very-possibly a mixed-manic episode with a heavy preponderance of depressive symptoms. The maprotiline was combined with mirtazapine, sodium valproate and aripiprazole.

Absolute

As with other antidepressants, maprotiline increased the risk compared to placebo of suicidal thinking and behavior in children, adolescents and young adults in short-term studies of major depressive disorder and other psychiatric disorders. Anyone considering the use of maprotiline or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Maprotiline is not approved for use in pediatric patients.

Pregnancy and lactation

Reproduction studies have been performed in female laboratory rabbits, mice, and rats at doses up to 1.3, 7, and 9 times the maximum daily human dose respectively and have revealed no evidence of impaired fertility or harm to the fetus due to maprotiline. There are, however, no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Maprotiline is excreted in breast milk. At steady-state, the concentrations in milk correspond closely to the concentrations in whole blood. Caution should be exercised when maprotiline hydrochloride is administered to a nursing woman.

Side effects

The side-effect profile is comparable to other TCAs and TeCAS and many of the following are due to anticholinergic and antihistamine effects. Most often seen are:
Maprotiline causes a strong initial sedation and is therefore indicated to treat agitated patients or those with suicidal risks. It causes anticholinergic side effects with much lower incidence than amitriptyline. Originally, the manufacturer claimed that maprotiline is better tolerated than other TCAs and TeCAs. However, seizures, leukopenia and skin reactions occur more often with maprotiline than with comparable drugs. Indeed, seizures are greater risk for concern with maprotiline than with all other tricyclic antidepressants, including clomipramine. It should thus be prescribed with particular, if not extreme, caution to people with a history of epilepsy/seizures of any other kind. In any case, the total daily dose should be kept to ≤ 225 milligrams.
Maprotiline has no known potential for abuse and psychological dependence.

Withdrawal

Withdrawal symptoms frequently seen when treatment with maprotiline is stopped abruptly can be avoided by reducing the daily dose of maprotiline gradually by approximately 25% each week. If treatment has to be stopped at once for medical reasons, the use of a benzodiazepine for a maximum of 4 weeks as needed will usually suppress withdrawal symptoms.

Interactions

Maprotiline does have a wide range of possible interactions. Some are typical for TCAs and TeCAs, others are caused by specific metabolic effects of maprotiline:
Increased drug actions:
  • Other antidepressants, barbiturates, narcotics, sedating antihistamines, anticonvulsive drugs, alcohol resulting in increased central depression and necessitating some caution when using any of these drugs alongside maprotiline
  • Drugs with potential anti-muscarinic/anti-cholinergic activity resulting in increased anti-muscarinic effects
  • Sympathomimetics sympathomimetic effects increased
  • Nitrates and antihypertensives increased antihypertensive action with pronounced fall in blood pressure
Although concurrent administration of tricyclic antidepressants and MAOIs has been considered particularly dangerous, even fatal, across various medical and pharmaceutical lines across the decades, the premise for this line of thinking, although commonly accepted, may be erroneous. Specialist-research into this and practical clinical experience involving the co-administration of tricyclics and MAOIs have suggested that it is only tricyclics with strong specific serotonin-reuptake inhibitory action that are dangerous to give in combination with MAOIs. Other antidepressants; which may or may not have a significant serotonergic background otherwise but either way lack in particularly appreciable reuptake-inhibition therein specifically ; may be safe to take alongside MAOIs, where the likes of venlafaxine, SSRIs and clomipramine are not. With maprotiline, this has been demonstrated to be the case with moclobemide, a drug it is often compared and considered somewhat analogous to, and, tentatively, brofaromine. Moclobemide specifically, however, may increase maprotiline plasma-levels and may necessitate dose-modification.
In any case, however, it is very-strongly advised that an MAOI is added to the tricyclic and not the other way around, as adding a tricyclic to an existing treatment-regime involving an MAOI may significantly increase the risk of going into hypertensive crisis.
Decreased drug actions:
  • Guanethidine, reserpine, guanfacine: anti-hypertensive effects decreased
  • Clonidine: anti-hypertensive effects decreased and risk of rebound hypertension.
Other types of interaction:
  • Drugs which induce certain enzymes in the liver, e.g., barbiturates, phenytoin, carbamazepine and oral anti-conceptive drugs, enhance the elimination of maprotiline and decrease its antidepressant effects. Additionally the blood-concentrations of phenytoin or carbamazepine may be increased, leading to a higher incidents of side effects.
  • The concomitant use of maprotiline and neuroleptics can lead to increased maprotiline blood-levels and to seizures. Combining maprotiline and thioridazine could induce severe arrhythmias.
  • Additionally, increased blood-levels of maprotiline are possible, if certain beta-blocking agents are given concomitantly.
  • Maprotiline may amplify the actions of coumarin-type anticoagulants. The plasma-prothrombin-activity must be assessed closely in order to avoid overt bleedings.
  • Maprotiline can increase the actions of oral antidiabetic drugs and insulin. Diabetic patients should have regular assessments of their blood-glucose-levels.
  • The concomitant application with fluoxetine or fluvoxamine may lead to significantly increased plasma-levels of maprotiline, with a correspondingly incidence of maprotiline side effects. Owing to the long half-lives of fluoxetine and fluvoxamine, this effect may persist for quite-some time.