Professional Information

Maprotiline (Systemic)

VA CLASSIFICATION
Primary: CN609
Secondary: CN103

Commonly used brand name(s): Ludiomil.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

Category:

Antidepressant—

antineuralgic^{12}—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Bipolar disorder, depressed type (treatment)
Depressive disorder, major (treatment) or
Dysthymia (treatment)—Maprotiline is indicated for the treatment of depressive illness in patients with major depressive disorder ^{11}, dysthymic disorder, or bipolar disorder, depressed type ^{10} ^{15} ^{16} ^{17} ^{18} ^{30} ^{31}.

Anxiety associated with mental depression (treatment)—Maprotiline is also indicated for the management of anxiety associated with mental depression ^{10} ^{15} ^{16} ^{17} ^{18} ^{30} ^{31}.

[Pain, neurogenic (treatment)]¹—Maprotiline is used to treat some types of chronic pain ^{12}.

¹ Not included in Canadian product labeling.

Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    313.87 ^{15} ^{17} ^{18}

Mechanism of action/Effect:

A tetracyclic antidepressant, maprotiline is thought to increase the synaptic concentration of norepinephrine in the central nervous system (CNS) by blocking its re-uptake by the presynaptic neuronal membrane. No effect on serotonin re-uptake has been observed. Recent research has suggested that after long-term treatment with antidepressants, changes in postsynaptic beta-adrenergic receptor sensitivity and enhancement of response to alpha-adrenergic and serotonergic stimulation may contribute to the mechanism of antidepressant action. Antidepressants may produce a downregulation (desensitization) of presynaptic alpha ₂ receptors, equilibrating the noradrenergic system, and thus correcting the dysregulated output of depressed patients. ^{09}

Absorption:

Completely absorbed following oral administration ^{27} ^{29}.

Protein binding:

High (88%) ^{09} ^{16} ^{29}.

Biotransformation:

Hepatic ^{29}.

Half-life:

Elimination—27 to 58 hours ^{06} ^{29} (average 43 hours) ^{06}.

Active metabolite—60 to 90 hours ^{01}.

Onset of action:

For desired therapeutic effect, up to 2 or 3 weeks, but sometimes within 7 days ^{15} ^{17} ^{18}.

Time to peak concentration:

12 hours ^{26} ^{30} ^{31}.

Elimination:
    Biliary—About 30%, in feces ^{15} ^{29}.
    Renal ^{15}—About 65%, mostly as glucuronide metabolites.

Precautions to Consider

Note: The similarity of pharmacological effects of maprotiline and tricyclic antidepressants suggests that the same considerations and precautions be observed in the use of both medications. Therefore, until additional specific clinical information on maprotiline is available, certain precautionary guidelines for tricyclic antidepressants are included for consideration.

Carcinogenicity

No evidence of carcinogenicity was found in studies of animals given large daily doses of maprotiline for up to 1 year ^{15} ^{17} ^{18}.

Mutagenicity

No evidence of mutagenicity was found in offspring of female mice mated with male mice treated with up to 60 times the maximum daily human dose ^{15} ^{17} ^{18}.

Pregnancy/Reproduction

Pregnancy—
Adequate and well-controlled studies in humans have not been done ^{15} ^{17} ^{18}.

Studies in animals have not shown that maprotiline causes adverse effects on the fetus ^{15} ^{17} ^{18}.

FDA Pregnancy Category B ^{15} ^{17} ^{18} ^{30} ^{31}.

Breast-feeding

Maprotiline is distributed into breast milk in the same concentration as in blood ^{10} ^{15} ^{17} ^{18} ^{30} ^{31}.

Pediatrics

Appropriate studies on the relationship of age to the effects of maprotiline have not been performed in children up to 18 years of age. Safety and efficacy have not been established. ^{15} ^{17} ^{18} ^{30} ^{31}

Geriatrics

Elderly patients are more likely to exhibit increased dose sensitivity to the anticholinergic, sedative, and hypotensive effects of maprotiline; therefore, a lower initial dose should usually be used and the dosage maintained at the lowest effective level ^{02}. Careful monitoring is necessary to maintain optimum therapeutic serum concentrations in the elderly. Orthostatic hypotension, although rare, may occur in elderly patients and caution must be observed to prevent falls. ^{01}

Dental

The peripheral anticholinergic effects of maprotiline may decrease or inhibit salivary flow, especially in middle-aged or elderly patients, thus contributing to the development of caries, periodontal disease, oral candidiasis, and discomfort.

Although rarely reported, the blood dyscrasia–causing effects of maprotiline may result in an increased incidence of microbial infection, delayed healing, and gingival bleeding. If agranulocytosis, eosinophilia, purpura, or thrombocytopenia occurs, dental work should be deferred until blood counts have returned to normal. Patient instruction in proper oral hygiene should include caution in use of regular toothbrushes, dental floss, and toothpicks.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.
Although not all of the following interactions have been documented to pertain specifically to maprotiline, a potential exists for their occurrence because of the close similarity of maprotiline's pharmacological effects to those of tricyclic antidepressants.

» Alcohol^{09}^{15}^{16}^{20}^{29} or
» CNS depression–producing medications, other^{09}^{15}^{16}^{29} (see Appendix II )    (concurrent use with maprotiline may result in serious potentiation of CNS depressant effects)

Anticholinergics or other medications with anticholinergic activity^{09}^{15}^{16}^{17}^{18}^{29}^{30}^{31} (see Appendix II ) or
Antihistamines^{09}    (concurrent use may potentiate the anticholinergic effects of either these medications or maprotiline; dosage adjustments may be necessary)

Anticonvulsants^{09}    (maprotiline may enhance CNS depression, lower the seizure threshold, and decrease the effects of the anticonvulsant medication)

Antidepressants, tricyclic^{25}^{32} or
Bupropion^{21}^{22}^{25}^{32} or
Clozapine^{24}^{32} or
Haloperidol^{09}^{25}^{32} or
Loxapine^{09}^{25}^{32} or
Molindone^{09}^{25}^{32} or
Phenothiazines^{09}^{15}^{17}^{18}^{25}^{32} or
Pimozide^{14}^{25}^{32} or
Thioxanthenes^{09}^{25}^{32} or
Trazodone^{25}^{32}    (concurrent use may prolong and intensify the anticholinergic and sedative effects of either these medications or maprotiline; in addition, these medications may increase the risk of seizures by lowering the seizure threshold, and should be added or withdrawn with caution)

Cimetidine^{15}^{17}^{18}^{29}^{30}^{31}    (concurrent use may increase plasma concentrations of maprotiline; dosage adjustment of maprotiline may be necessary when cimetidine therapy is initiated or discontinued)

Clonidine or
Guanadrel or
Guanethidine^{09}^{15}^{16}^{18}^{19}^{20}^{29}^{30}^{31}    (antihypertensive effects may be decreased when these medications are used concurrently with maprotiline)

    (concurrent use of clonidine with maprotiline may result in serious potentiation of CNS depressant effects)

Contraceptives, oral, estrogen-containing or
Estrogens^{09}^{20}^{29}    (concurrent use of large doses of estrogens with tricyclic antidepressants may potentiate antidepressant side effects and reduce the therapeutic effects of the tricyclic antidepressants; although not documented, similar effects may occur with maprotiline, a tetracyclic antidepressant)

Fluoxetine^{23}^{30}^{31}    (plasma concentrations of tricyclic antidepressants may be increased twofold or more when fluoxetine is used concurrently; although not documented, similar increases may occur with maprotiline, a tetracyclic antidepressant; some clinicians recommend dosage reductions of maprotiline of 50% or greater if used concomitantly with fluoxetine ^{25})

» Monoamine oxidase (MAO) inhibitors,^{09}^{15}^{16}^{17}^{18}^{29}^{30}^{31} including furazolidone, procarbazine, and selegiline    (concurrent use with maprotiline is generally not recommended, especially on an outpatient basis, as hyperpyretic episodes, severe convulsions, hypertensive crises, and death have resulted in a small number of patients from concurrent use with tricyclic antidepressants; a minimum of 14 days should elapse between discontinuing MAO inhibitors and initiating maprotiline therapy)

Naphazoline, ophthalmic or
Oxymetazoline, nasal or
Phenylephrine, nasal or ophthalmic or
Xylometazoline, nasal    (if significant systemic absorption occurs, concurrent use with maprotiline may potentiate pressor effects of these medications)

» Sympathomimetics^{09}^{15}^{16}^{17}^{18}^{19}^{29}^{30}^{31}    (concurrent use with maprotiline may potentiate cardiovascular effects, possibly resulting in arrhythmias, tachycardia, or severe hypertension or hyperpyrexia; phentolamine can control the adverse reaction)

    (significant systemic absorption of ophthalmic epinephrine may also potentiate cardiovascular effects; also, local anesthetics with vasoconstrictors should be avoided or a minimal amount of the vasoconstrictor should be used with the local anesthetic)

    (concurrent use with maprotiline may decrease the pressor effects of ephedrine and mephentermine)

Thyroid hormones^{15}^{16}^{18}^{20}^{29}^{30}^{31}    (concurrent use with maprotiline may enhance the possibility of cardiac arrhythmias; dosage adjustments may be necessary)

Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).

Except under special circumstances, this medication should not be used when the following medical problems exist:
» Myocardial infarction, during the acute recovery period^{15}^{16}^{17}^{18}^{29}^{30}^{31}
» Seizure disorders, including epilepsy, or history of seizures^{15}^{16}^{17}^{18}^{29}^{30}^{31}    (risk of seizures is increased ^{04})

Risk-benefit should be considered when the following medical problems exist
» Alcoholism, active    (increased risk of seizures and CNS depression)

» Asthma or
» Blood disorders^{16} or
» Glaucoma, angle-closure^{15}^{16}^{17}^{18}^{30}^{31} or
» Increased intraocular pressure^{15}^{16}^{17}^{18}^{29}^{30}^{31} or
» Urinary retention, or history of^{15}^{16}^{17}^{18}^{29}^{30}^{31}    (may be exacerbated)

» Bipolar disorder    (swing to hypomanic or manic phase may be accelerated and rapid cycling between mania and depression may be induced by maprotiline ^{11} ^{15} ^{16} ^{17} ^{18} ^{29} ^{30} ^{31})

» Cardiovascular disorders^{15}^{16}^{17}^{18}^{29}^{30}^{31}    (increased risk of conduction defects, arrhythmias, myocardial infarction, strokes, and tachycardia)

Gastrointestinal disorders    (risk of paralytic ileus)

» Hepatic function impairment^{15}    (metabolism may be altered)

» Hyperthyroidism^{15}^{16}^{18}^{29}^{30}^{31}    (increased risk of cardiovascular toxicity)

» Myocardial infarction, history of^{15}^{17}^{18}^{29}^{30}^{31}    (increased risk of recurrence)

Prostatic hypertrophy^{16}^{29}    (risk of urinary retention)

» Schizophrenia    (psychosis may be aggravated ^{15} ^{17} ^{18} ^{29})

Sensitivity to maprotiline or tricyclic antidepressants^{15}^{16}^{17}^{18}^{29}^{30}^{31}

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Blood cell counts    (may be required at periodic intervals during long-term therapy; in patients with sore throat and fever, leukocyte and differential counts may be necessary; maprotiline should be discontinued if there is evidence of pathologic neutrophil depression ^{15} ^{16} ^{17} ^{18} ^{30} ^{31})

Blood pressure determinations^{16} and
Cardiac function monitoring^{16} and
Hepatic function determinations^{16}    (may be required at periodic intervals during therapy to detect development of adverse effects that may not be evident to the patient)

Careful observation for possibility of drug-induced acceleration to hypomania or mania^{01}^{29}^{30}^{31}    (recommended periodically although most patients respond favorably to maprotiline when it is used to treat the depressed phase of bipolar disorder ^{01})

Careful observation for possibility of suicide attempt    (suicidal tendencies may persist in some severely depressed patients during the early phases of therapy until significant remission of depression occurs ^{29} ^{30} ^{31})

Side/Adverse Effects

Note: Although not all of the following side effects have been attributed specifically to maprotiline, a potential exists for their occurrence as with the tricyclic antidepressants.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent

Skin rash, redness, swelling, or itching^{01}^{03}^{16}^{17}^{18}

Incidence less frequent

Constipation, severe —may lead to paralytic ileus^{15}^{16}^{17}^{18}

nausea or vomiting^{15}^{16}^{17}^{18}

seizures^{15}^{16}^{17}^{18}

shakiness or trembling^{15}^{17}^{18}

unusual excitement^{15}

weight loss^{13}^{15}

Note: Seizures may occur in patients with or without a history of seizures, usually with doses above 200 mg a day. The lowest effective maintenance dose is recommended to reduce further risk. Drugs that alter seizure threshold should be added to or withdrawn from maprotiline regimen with caution. ^{04} ^{05} ^{08}

Incidence rare

Agranulocytosis^{15}^{16}^{17}^{18} (sore throat and fever)—rarely reported for maprotiline, but has occurred with tricyclic antidepressants

anticholinergic effect (difficulty in urinating)^{15}^{16}^{17}^{18}

breast enlargement —in males and females^{10}^{15}^{16}^{17}^{18}

confusion —especially in elderly^{15}^{16}^{17}^{18}

hallucinations^{15}^{16}^{17}^{18}

hypotension^{15}^{16}^{17}^{18} (fainting)

inappropriate secretion of milk —in females^{10}^{15}^{16}^{17}^{18}

irregular heartbeat^{15}^{16}^{17}^{18}

jaundice^{15}^{16}^{17}^{18} , cholestatic (yellow eyes or skin)

swelling of testicles^{10}^{15}^{16}^{17}^{18}

Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent

Blurred vision^{15}^{16}^{17}^{18}

dizziness^{15}^{16}^{17}^{18} or lightheadedness —especially in the elderly

drowsiness^{15}^{16}^{17}^{18}

dryness of mouth^{15}^{16}^{17}^{18}

headache^{15}^{16}^{18}

impotence (decreased sexual ability)^{25}^{26}

increased or decreased sexual drive^{25}^{26}

tiredness or weakness^{15}^{16}^{17}^{18}

Incidence less frequent

Constipation, mild ^{15}^{16}^{17}^{18}

diarrhea^{15}^{16}^{17}^{18}

heartburn^{16}^{17}^{18}

increased appetite and weight gain^{15}^{16}^{17}^{18} —related to carbohydrate craving^{07}

increased sensitivity of skin to sunlight^{15}^{16}^{17}^{18}

increased sweating^{15}^{16}^{17}^{18}

insomnia^{15}^{16}^{17}^{18} (trouble in sleeping)

weight loss^{13}^{15}^{16}^{17}^{18}

Overdose
For specific information on the agents used in the management of maprotiline overdose, see:
   • Barbiturates (Systemic) monograph;
   • Benzodiazepines (Systemic) monograph;
   • Charcoal, Activated (Oral-Local) monograph;
   • Corticosteroids—Glucocorticoid Effects (Systemic)monograph;
   • Digitalis Glycosides (Systemic) monograph;
   • Phenytoin in Anticonvulsants, Hydantoin (Systemic) monograph;
   • Propranolol in Beta-adrenergic Blocking Agents (Systemic) monograph; and/or
   • Sodium Bicarbonate (Systemic) monograph.
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Coma^{15}^{16}^{17}^{18}

convulsions^{15}^{16}^{17}^{18}

dizziness, severe^{16}

drowsiness, severe^{15}^{17}^{18}

fast or irregular heartbeat^{15}^{16}^{17}^{18}

fever^{15}^{16}^{17}

muscle stiffness or weakness, severe^{15}^{16}

restlessness or agitation^{15}^{16}

trouble in breathing^{16}

vomiting^{15}^{16}^{17}^{18}

Note: Risk of seizures, respiratory complications, and cardiotoxicity is greater with maprotiline than with tricyclic antidepressants, and duration of comatose state and QRS complex is longer ^{06}.

Treatment of overdose
There is no specific antidote for maprotiline overdose ^{15} ^{16} ^{17} ^{18}. The following steps of supportive and symptomatic treatment may be considered:

To decrease absorption:
Emptying stomach with emetic and/or lavage ^{15} ^{16} ^{17} ^{18}.

Administering activated charcoal slurry ^{16} followed by a stimulant cathartic.

Specific treatment:
For circulatory collapse—Administering intravenous fluids, oxygen, and corticosteroids ^{15} ^{16} ^{17} ^{18}.

For congestive heart failure—Digitalizing rapidly ^{15} ^{17} ^{18}.

For cardiac arrhythmias—Alkalinizing blood with sodium bicarbonate. Arrhythmias refractory to sodium bicarbonate may be treated with phenytoin. Propranolol may be used with caution.

For seizures and hyperirritability—Administering carefully titrated parenteral benzodiazepines ^{24} or barbiturates. However, barbiturates should not be used if monoamine oxidase inhibitors have been used in recent therapy. Also, barbiturates may cause respiratory depression, especially in children. Equipment should be available to provide artificial ventilation and resuscitation. Administration of physostigmine salicylate is not recommended because of an increase in the risk of seizures. ^{06} ^{15} ^{17} ^{18}

Supportive care:
Controlling hyperpyrexia by any available means, including ice packs if necessary ^{15} ^{16} ^{17} ^{18}.

Patients in whom intentional overdose is known or suspected should be referred for psychiatric consultation.

Note: Dialysis of maprotiline has not been successful because of its high protein binding ^{15} ^{16} ^{17} ^{18}.

Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Maprotiline (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to maprotiline or tricyclic antidepressants

Use in the elderly—Elderly patients may be more prone to develop anticholinergic, sedative, and hypotensive effects

Dental—Dry mouth may cause caries, oral candidiasis, periodontal disease, and discomfort; rare blood dyscrasias may result in increased incidence of microbial infection, delayed healing, and gingival bleeding
Other medications, especially alcohol or other CNS depression–producing medications, MAO inhibitors, or sympathomimetics
Other medical problems, especially active alcoholism, asthma, bipolar disorder, blood disorders, cardiovascular disorders, glaucoma, hepatic function impairment, hyperthyroidism, increased intraocular pressure, schizophrenia, seizure disorders, or urinary retention

Proper use of this medication
» Compliance with therapy

» May require up to 2 to 3 weeks of therapy to obtain optimal antidepressant effects

» Proper dosing
Missed dose: If dosing schedule is:

• More than one dose a day—Taking as soon as possible; if almost time for next dose, skipping missed dose; going back to regular dosing schedule; not doubling doses

• One dose a day at bedtime—Not taking missed dose following morning; checking with doctor

» Proper storage

Precautions while using this medication
Regular visits to physician to check progress during therapy

» Avoiding the use of alcohol or other CNS depressants during maprotiline therapy ^{15} ^{16} ^{17} ^{18}

» Possible drowsiness; caution when driving, using machines, or doing other things requiring alertness ^{15} ^{16} ^{17} ^{18}

» Possible dizziness or lightheadedness; caution when getting up suddenly from a lying or sitting position

» Possible dryness of mouth; using sugarless gum or candy, ice, or saliva substitute for relief; checking with physician or dentist if dry mouth continues for more than 2 weeks

» Caution if any kind of surgery, dental treatment, or emergency treatment is required

» Checking with physician before discontinuing medication; gradual dosage reduction may be needed

Side/adverse effects
Anticholinergic, sedative, and hypotensive effects more likely to occur in the elderly

Precautions followed for 3 to 7 days after discontinuing medication

Signs of potential side effects, especially skin rash, redness, swelling, or itching; severe constipation; convulsions; nausea or vomiting; shakiness or trembling; unusual excitement; weight loss; agranulocytosis; anticholinergic effect; breast enlargement; confusion; hallucinations; hypotension; inappropriate secretion of milk; irregular heartbeat; jaundice; or swelling of testicles

General Dosing Information
Dosage of maprotiline must be individualized for each patient by titration ^{16}.

Correlations between plasma concentration, clinical response, side effects, and toxicity have not been established.

Some clinicians recommend that for maintenance therapy, the optimal daily dose may be reduced somewhat, sometimes given as a single dose at bedtime, and often continued for 6 months to 1 year. (A divided dose may be preferred for geriatric, adolescent, or cardiovascular patients.) In patients with recurrent depression, however, continuation of the full treatment dose during maintenance therapy may be optimal. ^{28}

The single daily dose at bedtime is useful when side effects such as excessive drowsiness or dizziness might be bothersome or dangerous during working hours.

A gradual reduction in dosage is recommended when this medication is to be discontinued.

Potentially suicidal patients should not have access to large quantities of this medication since depressed patients, particularly those who may use alcohol excessively, may continue to exhibit suicidal tendencies until significant improvement occurs. Some clinicians recommend that the patient be supplied with the least amount of medication necessary for satisfactory patient management. ^{15} ^{17} ^{18}

Oral Dosage Forms

MAPROTILINE HYDROCHLORIDE TABLETS USP

Usual adult and adolescent dose
Antidepressant
Oral, initially 25 to 75 mg a day, in divided doses, for at least two weeks, the dosage being adjusted gradually by 25 mg a day as needed and tolerated ^{15} ^{16} ^{17} ^{18} ^{29} ^{30} ^{31}.

Note: The effective maintenance dose is usually about 150 mg a day, often given once a day at bedtime ^{15} ^{16} ^{17} ^{18} ^{30} ^{31}.

Usual adult prescribing limits
Outpatients: Up to 150 mg a day ^{15} ^{16} ^{17} ^{18} ^{30} ^{31}.

Hospitalized patients: Up to 225 mg a day ^{15} ^{16} ^{17} ^{18} ^{30} ^{31}.

Usual pediatric dose
Children up to 18 years of age: Safety and efficacy have not been established ^{15} ^{17} ^{18} ^{30} ^{31}.

Usual geriatric dose
Initial: Oral, 25 mg a day ^{15} ^{17} ^{18} ^{30} ^{31}.

Maintenance: Oral, 50 to 75 mg a day ^{15} ^{16} ^{17} ^{18} ^{29} ^{30} ^{31}.

Strength(s) usually available
U.S.—

25 mg (Rx) [Ludiomil (lactose)][Generic]

50 mg (Rx) [Ludiomil (lactose)][Generic]

75 mg (Rx) [Ludiomil (lactose)][Generic]

Canada—

10 mg (Rx) [Ludiomil (lactose)]

25 mg (Rx) [Ludiomil (lactose) (tartrazine)]

50 mg (Rx) [Ludiomil (lactose)]

75 mg (Rx) [Ludiomil (scored) (lactose)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a well-closed container.

Auxiliary labeling:
   • May cause drowsiness.
   • Avoid alcoholic beverages.

Revised: 08/07/1998

References

Panelist comment, DI 1988.

Manufacturer comment, 1986.

Schmidt LG, et al. Adverse drug reactions to first- and second-generation antidepressants: A critical evaluation of drug surveillance data. Br J Psychiatry 1986; 148: 38-43.

Bernard P, Levine M. Maprotiline-induced seizures. Southern Med J 1986; 79: 1179-80.

Dessain EC, et al. Maprotiline treatment in depression. Arch Gen Psychiatry 1986; 43: 86-90.

Hayes PE, Kristoff CA. Drug review: Adverse reactions to five new antidepressants. Clin Pharm 1986; 5: 471-80.

Nakra BRS, Grossberg GT. Psychosomatics 1986; 27: 376-7.

Jabbari BB, et al. Incidence of seizures with tricyclic and tetracyclic antidepressants. Arch Neurol 1985; 42: 480-1.

Bryant SG, Brown CS. Current concepts in clinical therapeutics: Major affective disorders, Part 1. Therapy review. Clin Pharm 1986; 5: 304-18.

Ludiomil (Ciba). In: Physicians' desk reference. 40th ed. 1986. Oradell, NJ: Medical Economics Company, 1986.

Panelist comment, 5/88.

Panelist comment, 5/88.

Manufacturer comment, 5/88.

Panelist comment, 5/88.

Ludiomil (Ciba). In: Physicians' desk reference. 44th ed. 1990. Oradell, NJ: Medical Economics Company, 1990: 859-60.

Ludiomil product monograph (Ciba-Geigy—Canada). Rev 12/84, Rec 3/90.

Maprotiline package insert (Mylan—US), Rev 2/88, Rec 3/89.

Maprotiline package insert (Bolar—US), Rev 12/87, Rec 11/88.

Tatro DS, editor, Drug interaction facts, 1990. St Louis: Facts and comparisons, 1990: 350, 678.

Shinn AF, Shewsbury RP, EDI, Evaluation of drug interactions. 3rd ed. St Louis: Mosby, 1985: 291, 294, 318-9, 596.

Reviewer comment, 8/89.

Reviewer comment, 10/30/90.

Fluoxetine package insert (Prozac, Dista—US), Rev 6/89.

Panel comment, 5/91.

Panel consensus, 5/91.

Ludiomil package insert (Ciba—US), Rev 1/91, Rec 5/91.

Manufacturer comment, 5/91.

Panel comment, 5/91.

Ludiomil package insert (Ciba—Canada), Rev 5/17/90, Rec 12/91.

Maprotiline package insert (Mylan—US), Rev 8/92, Rec 9/93.

Ludiomil package insert (Ciba—US), Rev 2/92, Rec 3/94.

Reviewers' responses to Psychiatric Disease Advisory Panel Memo #6 of 9/16/91.

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