VA Class:CN609
Maprotiline hydrochloride is a tetracyclic antidepressant that is pharmacologically similar to the tricyclic antidepressants.
Maprotiline hydrochloride is used in the treatment of depressive affective (mood) disorders, including dysthymic disorder (depressive neurosis) and major depressive disorder. The drug has been used for the depressive phase of bipolar disorder; however, hypomanic or manic episodes may occur when the drug is given to patients with this disorder and other antidepressants (e.g., bupropion, selective serotonin-reuptake inhibitors) generally are preferred when an antidepressant is considered necessary in such patients. (See Considerations in Choosing Therapy for Depressive Episodes under Uses: Bipolar Disorder, in Lithium Salts 28:28.) Maprotiline is effective for the relief of anxiety associated with depression. Most studies comparing maprotiline with amitriptyline or imipramine in the treatment of patients with various types of depression have not demonstrated superiority of maprotiline over these tricyclic antidepressants. Although maprotiline has been reported to have a slightly more rapid onset of action than either amitriptyline or imipramine in some studies, this finding has not been adequately established.
For further information on treatment of major depressive disorder and considerations in choosing the most appropriate antidepressant for a particular patient, including considerations related to patient tolerance, patient age, and cardiovascular, sedative, and suicidal risks, see Considerations in Choosing Antidepressants under Uses: Major Depressive Disorder, in the Tricyclic Antidepressants General Statement 28:16.04.28.
Maprotiline hydrochloride is administered orally. Although maprotiline has been administered in 3 divided doses throughout the day, it is long-acting and the entire daily dose may be administered at one time.
Dispensing and Administration Precautions
Dispensing errors have occurred because of the similarity in spelling between Ludiomil® (the former trade name for maprotiline hydrochloride; no longer commercially available under this trade name in the US) and Lamictal® (the trade name for lamotrigine, an anticonvulsant).101, 102 Therefore, extra care should be exercised in ensuring the accuracy of both oral and written prescriptions for Ludiomil® and Lamictal®.101, 102 The manufacturer of Lamictal® (GlaxoSmithKline) recommends that clinicians consider including the intended use of the particular drug on the prescription, in addition to alerting patients to carefully check the drug they receive and promptly bring any question or concern to the attention of the dispensing pharmacist.101 The manufacturer of Lamictal® also recommends that pharmacists assess various measures of avoiding dispensing errors and implement them as appropriate (e.g., by computerized filling and handling of prescriptions, patient counseling).102 (See Cautions.)
There is a wide range of dosage requirements, and dosage of maprotiline hydrochloride must be carefully individualized. The manufacturer suggests that the risk of seizures may be decreased by initiating therapy with low dosages of the drug. Initial dosages should be low, generally 75 mg daily in outpatients with mild to moderate depression, although a lower initial dosage may be used in some patients (e.g., geriatric patients). Because of the long elimination half-life of maprotiline, the initial dosage should be maintained for 2 weeks. Depending on tolerance and response, the daily dose may then be gradually increased in 25-mg increments. In most outpatients, a maximum dosage of 150 mg daily will be effective; it is recommended that this dosage be exceeded only in very severely depressed patients. Severely depressed hospitalized patients under close supervision may generally be given higher dosages than outpatients; such patients may be given an initial dosage of 100-150 mg daily which may be increased cautiously. Most hospitalized patients with moderate to severe depression will respond to a dosage of 150 mg daily, but dosages as high as 225 mg daily may be necessary in some patients; dosage should not exceed 225 mg daily. Geriatric patients (i.e., patients older than 60 years of age) should usually be given lower than average dosages; 50-75 mg daily is generally satisfactory for these patients. Antidepressant effects usually occur within 2-3 weeks in most patients who respond to maprotiline therapy and may occur within 3-7 days.
After symptoms are controlled, dosage of maprotiline hydrochloride should be gradually reduced to the lowest level that will maintain relief of symptoms, generally 75-150 mg daily. To minimize the risk of seizures, maintenance dosage should be less than 200 mg daily.100
Patients should be monitored for possible worsening of depression, suicidality, or unusual changes in behavior, especially at the beginning of therapy or during periods of dosage adjustment.103, 104, 105 (See Cautions: Precautions and Contraindications and also see Cautions: Precautions and Contraindications, in the Tricyclic Antidepressants General Statement 28:16.04.28.)
Maprotiline hydrochloride shares the toxic potentials of the tricyclic antidepressants, and the usual precautions of tricyclic antidepressant administration should be observed. (See Cautions in the Tricyclic Antidepressants General Statement 28:16.04.28.)
Precautions and Contraindications
Worsening of depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior may occur in both adult and pediatric (see Cautions: Pediatric Precautions) patients with major depressive disorder or other psychiatric disorders, whether or not they are taking antidepressants.103, 104, 105, 106 This risk may persist until clinically important remission occurs with therapy.104 Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.103, 104, 105 However, there has been a long-standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment.104 Pooled analyses of short-term, placebo-controlled studies of antidepressants (i.e., selective serotonin-reuptake inhibitors and other antidepressants) have shown an increased risk of suicidality in children, adolescents, and young adults (18-24 years of age) with major depressive disorder and other psychiatric disorders.103, 104 An increased suicidality risk was not demonstrated with antidepressants compared with placebo in adults older than 24 years of age, and a reduced risk was observed in adults 65 years of age or older.103, 104
The US Food and Drug Administration (FDA) recommends that all patients being treated with antidepressants for any indication be appropriately monitored and closely observed for clinical worsening, suicidality, and unusual changes in behavior, particularly during inititation of therapy (i.e., the first few months) and during periods of dosage adjustments.103, 104, 105 Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, also should be advised to monitor patients on a daily basis for the emergence of agitation, irritability, or unusual changes in behavior as well as the emergence of suicidality, and to report such symptoms immediately to a health-care provider.104, 105
Although a causal relationship between the emergence of symptoms such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, and/or mania and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.104, 105 Consequently, consideration should be given to changing the therapeutic regimen or discontinuing therapy in patients whose depression is persistently worse or in patients experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, particularly if such manifestations are severe, abrupt in onset, or were not part of the patient's presenting symptoms.104 FDA also recommends that the drugs be prescribed in the smallest quantity consistent with good patient management, in order to reduce the risk of overdosage.104
It is generally believed (though not established in controlled trials) that treating a major depressive episode with an antidepressant alone may increase the likelihood of precipitating a mixed or manic episode in patients at risk for bipolar disorder.104 Therefore, patients should be adequately screened for bipolar disorder prior to initiating treatment with an antidepressant; such screening should include a detailed psychiatric history (e.g., family history of suicide, bipolar disorder, and depression).104
Seizures have been reported in patients receiving maprotiline and have occurred principally in those with no previous history of seizures. Although most of the tricyclic antidepressants have been reported to induce seizures, it has generally been suggested that maprotiline may be associated with a higher incidence of seizures than the tricyclic antidepressants. The exact incidence of seizures associated with maprotiline remains to be clearly determined.100 Results of an analysis suggest that the incidence may be similar to that associated with tricyclic antidepressants when the currently recommended maprotiline dosage guidelines are followed but that the incidence is probably higher than that associated with tricyclic antidepressants when the current dosage guidelines are not followed.100 Maprotiline-induced seizures usually have occurred in patients receiving 200 mg or more daily; however, seizures have also occurred occasionally in patients receiving lower dosages of the drug, generally during early stages of therapy.100 Rapid dosage increases and/or high plasma concentrations of the drug do not appear to be directly related to seizure occurrence.100 Some clinicians suggest that accumulation of an unidentified long-acting metabolite of maprotiline may be responsible for the development of these seizures.100 Special caution is warranted in patients with a history of seizures or who may be predisposed to seizures because of age, disease, or injury. To minimize the risk of seizures, the lowest effective maintenance dosage should be used; administration of or alteration of concomitant therapy with other drugs known to lower the seizure threshold should be done with caution; and patients with abnormal EEGs should receive other antidepressants when possible.100
Because of the similarity in spelling between Ludiomil® (the former trade name for maprotiline hydrochloride; no longer commercially available under this trade name in the US) and Lamictal® (the trade name for lamotrigine, an anticonvulsant agent), several dispensing errors have been reported to the manufacturer of Lamictal® (GlaxoSmithKline).101, 102 These medication errors may be associated with serious adverse events either due to lack of appropriate therapy for seizures (e.g., in patients not receiving the prescribed anticonvulsant, lamotrigine, which may lead to status epilepticus) or, alternatively, to the risk of developing adverse effects (e.g., serious rash) associated with the use of lamotrigine in patients for whom the drug was not prescribed and consequently was not properly titrated.101, 102 Therefore, the manufacturer of Lamictal® cautions that extra care should be exercised in ensuring the accuracy of both oral and written prescriptions for Lamictal® and Ludiomil®.101, 102 The manufacturer also recommends that, when appropriate, clinicians might consider including the intended use of the particular drug on the prescription in addition to alerting patients to carefully check the drug they receive and promptly bring any question or concern to the attention of the dispensing pharmacist.101 The manufacturer also recommends that pharmacists assess the measures of avoiding dispensing errors and implement them as appropriate (e.g., placing drugs with similar names apart from one another in product storage areas, patient counseling).102
Safety and efficacy of maprotiline in children younger than 18 years of age have not been established.
FDA has determined that antidepressants increase the risk of suicidal thinking and behavior (suicidality) in children and adolescents with major depressive disorder and other psychiatric disorders.104, 107 The risk of suicidality for these drugs was identified in a pooled analysis of data from a total of 24 short-term, placebo-controlled studies of 9 antidepressants (i.e., selective serotonin-reuptake inhibitors [SSRIs] and other antidepressants) in over 4400 children and adolescents with major depressive disorder, obsessive-compulsive disorder (OCD), or other psychiatric disorders.104, 107 The analysis revealed a greater risk of adverse events representing suicidal behavior or thinking (suicidality) during the first few months of treatment in pediatric patients receiving antidepressants than in those receiving placebo.104, 107 The average risk of such events was 4% among children and adolescents receiving these drugs, twice the risk (2%) that was observed among those receiving placebo.104, 107 However, a more recent meta-analysis of 27 placebo-controlled trials of 9 antidepressants (i.e., SSRIs and others) in patients younger than 19 years of age with major depressive disorder, OCD, or non-OCD anxiety disorders suggests that the benefits of antidepressant therapy in treating these conditions may outweigh the risks of suicidal behavior or suicidal ideation.106 No suicides occurred in these pediatric trials.104, 106, 107 Anyone considering the use of maprotiline in a child or adolescent for any clinical use must balance the potential risk of therapy with the clinical need.104, 105, 106, 107
The pharmacology of maprotiline is similar to that of the tricyclic antidepressants; the precise mechanism of antidepressant action is unclear. Like the tricyclics, maprotiline blocks the reuptake of norepinephrine at the neuronal membrane, possesses anticholinergic activity, and does not inhibit monoamine oxidase. However, maprotiline differs from most of the tricyclics in that it does not appear to influence the reuptake of serotonin.
Maprotiline has been reported to produce sedation in depressed patients and to reduce aggressive behavior in animals. Abnormal EEG patterns, including increases in theta and delta activity, decreases in fast beta activity, and variable effects on alpha wave activity may occur. Maprotiline may lower the seizure threshold, as do the tricyclics. (See Cautions: Precautions and Contraindications.)
Maprotiline shares the cardiovascular effects of the tricyclics and may cause ECG changes, tachycardia, and postural hypotension. Like the tricyclics, therapeutic doses of maprotiline do not affect respiration, but respiratory depression may occur following toxic doses. The effects of maprotiline on the endocrine system have not been evaluated.
Maprotiline hydrochloride is slowly but completely absorbed from the GI tract. Peak plasma concentrations of maprotiline occur 8-24 hours after a single oral dose. Following oral administration of single daily doses of 50 mg, 100 mg, or 150 mg of maprotiline hydrochloride, steady-state plasma drug concentrations are usually attained within 7 days and exhibit wide interpatient variation.
About 88% of maprotiline is bound to plasma proteins. Data from a patient who ingested a fatal overdosage of maprotiline hydrochloride indicate that the drug and its metabolites are distributed mainly to the liver, lungs, brain, and kidneys, with lower concentrations in the adrenal gland, heart, and muscle. Maprotiline is distributed into milk in concentrations similar to those present in maternal blood.
The plasma half-life of maprotiline averages 51 hours (range: 27-58 hours).
Maprotiline is slowly metabolized in the liver primarily to pharmacologically active desmethylmaprotiline, which may undergo further transformation, and to maprotiline- N -oxide. Approximately 60% of a dose of maprotiline hydrochloride is excreted in urine within 21 days primarily as conjugated metabolites; approximately 30% of the drug is excreted in feces.
Maprotiline hydrochloride is a dibenzo-bicyclo-octadiene derivative. The drug is a tetracyclic antidepressant which differs structurally from the tricyclic antidepressants in that it has an ethylene bridge in its center ring which results in a rigid flexure of its molecular skeleton. Maprotiline hydrochloride occurs as a white, crystalline powder and is slightly soluble in water. The drug has an apparent pKa of 10.2.
Maprotiline hydrochloride tablets should be stored in tight, light-resistant containers at 20-25°C.107
Additional Information
For further information on chemistry, pharmacology, pharmacokinetics, uses, cautions, acute toxicity, drug interactions, and dosage and administration of maprotiline, see the Tricyclic Antidepressants General Statement 28:16.04.28.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets | 25 mg* | Maprotiline Hydrochloride Tablets | |
50 mg* | Maprotiline Hydrochloride Tablets | |||
75 mg* | Maprotiline Hydrochloride Tablets |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
AHFS® Drug Information. © Copyright, 1959-2022, Selected Revisions January 1, 2009. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
100. Dessain EC, Schatzberg AF, Woods BT et al. Maprotiline treatment in depression: a perspective on seizures. Arch Gen Psychiatry . 1986; 43:86-90. [PubMed 3942475]
101. Pattishall EN. Dear healthcare provider letter regarding dispensing errors involving Lamictal® (lamotrigine). Research Triangle Park, NC: GlaxoSmithKline; undated.
102. Pattishall EN. Dear pharmacist letter: Dispensing errors alert. Research Triangle Park, NC: GlaxoSmithKline; 2001 Aug.
103. Food and Drug Administration. FDA news: FDA proposes new warnings about suicidal thinking, behavior in young adults who take antidepressant medications. Rockville, MD; 2007 May 2. From the FDA web site. [Web]
104. Food and Drug Administration. Antidepressant use in children, adolescents, and adults: class revisions to product labeling. Rockville, MD; 2007 May 2. From the FDA web site. [Web]
105. Food and Drug Administration. Revisions to medication guide: antidepressant medicines, depression and other serious mental illnesses and suicidal thoughts or actions. Rockville, MD; 2007 May 2. From the FDA web site. [Web]
106. Bridge JA, Iyengar S, Salary CB. Clinical response and risk for reported suicidal ideation and suicide attempts in pediatric antidepressant treatment: a meta-analysis of randomized controlled trials. JAMA . 2007; 297:1683-96. [PubMed 17440145]
107. Mylan Pharmaceuticals Inc. Maprotiline hydrochloride tablets prescribing information. Morgantown, WV. 2006 Feb.