Maprotiline Hydrochloride

Approved Medical Indications:

• Major Depressive Disorder (MDD):
  Treatment of depressive illness, especially where anxiety or agitation is present.
• Depressive Neuroses (Dysthymia):
  Treatment of chronic, low-grade depressive states.
• Reactive Depression:
  For situational or adjustment-related depressive states.
• Anxiety Associated with Depression:
  Effective where symptoms of anxiety are prominent in depressive patients.

Clinically Accepted Off-Label Uses:

• Chronic Neuropathic Pain (off-label):
  Occasionally used in the management of chronic neuropathic conditions due to its noradrenergic activity.

Route: Oral

Adults:

• Initial Dose:
  75 mg/day orally in divided doses or as a single dose at bedtime.
• Maintenance Dose:
  75 to 150 mg/day in divided doses or as a single evening dose.
  In severe cases, dosage may be increased cautiously to a maximum of 225 mg/day.
• Elderly Patients:
  Start with 25 mg/day; increase gradually based on response and tolerance.
  Maximum recommended dose: 75 mg/day.

Pediatrics:

• Safety and efficacy in children have not been established. Use is not recommended in pediatric patients.

Renal or Hepatic Impairment:

• Use with caution; dose reduction may be necessary.
  Monitor liver enzymes and renal function periodically during treatment.

Administration Notes:

• May be taken with or without food.
• Tablets should be swallowed whole with water.
• Dose should be individualized based on clinical response and side effect profile.

Maprotiline is a tetracyclic antidepressant that primarily acts as a selective norepinephrine reuptake inhibitor (NRI). It inhibits the reuptake of norepinephrine at presynaptic nerve endings in the central nervous system, increasing norepinephrine concentrations in the synaptic cleft and enhancing noradrenergic neurotransmission. This leads to improvement in depressive symptoms, particularly those with associated anxiety or agitation. It has weak serotonergic and anticholinergic properties but strong antihistaminic effects, which contribute to its sedative profile.

• Absorption: Well absorbed from the gastrointestinal tract.
• Bioavailability: ~66%
• Onset of Action: Clinical effects may begin within 1–2 weeks, full response by 3–4 weeks.
• Peak Plasma Levels: 12–24 hours post-dose
• Protein Binding: ~88%
• Distribution: Widely distributed; crosses the blood-brain barrier.
• Metabolism: Extensively metabolized in the liver via hydroxylation and demethylation; minor activity via CYP2D6.
• Half-Life: Approximately 43–60 hours (long half-life allows once-daily dosing).
• Excretion: Primarily excreted in urine as metabolites; ~2–5% excreted unchanged.

• Pregnancy:
  Not assigned a formal FDA pregnancy category (prior to FDA category retirement). Use only if potential benefit justifies the potential risk. Animal studies have shown embryotoxicity; limited human data are available.
• Lactation:
  Maprotiline is excreted into breast milk. Breastfeeding is not recommended due to potential for adverse effects in the infant (e.g., sedation, poor feeding, respiratory distress).

• Primary Class: Tetracyclic Antidepressant (TeCA)
• Subclass: Selective Norepinephrine Reuptake Inhibitor (NRI)

• Known hypersensitivity to maprotiline or other tetracyclic antidepressants
• Recent myocardial infarction
• History of seizures or epilepsy
• Severe hepatic or renal impairment
• Narrow-angle glaucoma
• Concurrent use with monoamine oxidase inhibitors (MAOIs) or within 14 days of discontinuing an MAOI
• Untreated hyperthyroidism or use with thyroid hormones (may increase arrhythmia risk)

• Seizure Risk:
  Maprotiline lowers the seizure threshold, especially at high doses or in patients with seizure history.
• Suicidality in Youth:
  Increased risk of suicidal thinking and behavior in adolescents and young adults with depression; close monitoring is necessary.
• Cardiac Effects:
  May cause arrhythmias, QT prolongation, or conduction abnormalities, especially in patients with pre-existing heart conditions.
• Sedation:
  Strong sedative effects due to antihistaminic activity. May impair alertness.
• Anticholinergic Effects:
  Dry mouth, blurred vision, constipation, and urinary retention, especially in elderly patients.
• Withdrawal Symptoms:
  Gradual dose tapering is recommended to avoid discontinuation syndrome (e.g., nausea, malaise, headache, rebound depression).
• Mania/Hypomania:
  May precipitate manic episodes in patients with bipolar disorder.

Common Adverse Effects:

• CNS: Drowsiness, dizziness, fatigue, agitation, tremor, insomnia
• GI: Dry mouth, constipation, nausea
• Autonomic: Blurred vision, urinary retention, orthostatic hypotension
• Weight: Weight gain or increased appetite

Serious and Rare Adverse Effects:

• Seizures (dose-dependent)
• Cardiac arrhythmias, conduction disturbances
• Agranulocytosis, leukopenia
• Hepatotoxicity, elevated liver enzymes
• Suicidal ideation (especially in adolescents)

Onset & Severity:

• Sedation and anticholinergic effects occur early; seizures and cardiac effects are dose-related.

Major Drug Interactions:

• MAO Inhibitors: Severe hypertensive crisis or serotonin syndrome; contraindicated.
• CNS Depressants (e.g., alcohol, benzodiazepines): Additive sedative effect.
• Anticholinergics (e.g., atropine): Increased risk of anticholinergic side effects.
• Anticonvulsants: May reduce seizure threshold.
• SSRIs (e.g., fluoxetine, paroxetine): May increase maprotiline levels by CYP2D6 inhibition.
• Sympathomimetics: Enhanced pressor effects (e.g., epinephrine).

Enzyme Systems Involved:

• Minor metabolism via CYP2D6; inhibitors of this enzyme may increase serum levels.

• Suicide Risk Warning:
  Updated labeling emphasizes monitoring for suicidality in younger patients.
• CNS Safety:
  Clinical use has declined due to the availability of newer antidepressants with better safety and seizure profiles.
• EMA/FDA Notes:
  Not first-line therapy; reserved for cases where tricyclic or SSRI therapy is not tolerated or effective.

• Temperature: Store below 25°C (77°F)
• Humidity & Light: Store in a dry place, protected from light and moisture
• Packaging: Keep in tightly closed container
• Handling Precautions:
• Keep out of reach of children
• Do not use expired or degraded tablets