Imipramine

Antidepressants increase the risk of suicidal thinking and behavior in children, adolescents, and young adults (18 to 24 years of age) with major depressive disorder (MDD) and other psychiatric disorders; consider risk prior to prescribing. Short-term studies did not show an increased risk in patients >24 years of age and showed a decreased risk in patients ≥65 years. Closely monitor patients for clinical worsening, suicidality, or unusual changes in behavior, particularly during the initial 1 to 2 months of therapy or during periods of dosage adjustments (increases or decreases); the patient's family or caregiver should be instructed to closely observe the patient and communicate condition with healthcare provider. A medication guide concerning the use of antidepressants should be dispensed with each prescription. Imipramine is FDA approved for the treatment of nocturnal enuresis in children ≥6 years of age.

May cause anticholinergic effects (constipation, xerostomia, blurred vision, urinary retention); use with caution in patients with decreased gastrointestinal motility, increased intraocular pressure, angle-closure glaucoma, paralytic ileus, urinary retention, BPH, xerostomia, or visual problems. The degree of anticholinergic blockade produced by this agent is high relative to other antidepressants.

May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery or driving). The degree of sedation is high relative to other antidepressants.

Bone fractures have been associated with antidepressant treatment. Consider the possibility of a fragility fracture if an antidepressant-treated patient presents with unexplained bone pain, point tenderness, swelling, or bruising (Rabenda 2013; Rizzoli 2012).

TCAs may rarely cause bone marrow suppression; monitor for any signs of infection and obtain CBC if symptoms (eg, fever, sore throat) are evident. Discontinue imipramine if there is evidence of pathological neutrophil depression.

May cause orthostatic hypotension (risk is very high relative to other antidepressants); use with caution in patients at risk of this effect or in those who would not tolerate transient hypotensive episodes (cerebrovascular disease, cardiovascular disease, hypovolemia, or concurrent medication use which may predispose to hypotension/bradycardia).

Has been associated with photosensitization; avoid excessive exposure to sunlight.

Potentially life-threatening serotonin syndrome (SS) has occurred with serotonergic agents (eg, SSRIs, SNRIs), particularly when used in combination with other serotonergic agents (eg, triptans, TCAs, fentanyl, lithium, tramadol, buspirone, St John's wort, tryptophan) or agents that impair metabolism of serotonin (eg, MAO inhibitors intended to treat psychiatric disorders, other MAO inhibitors [ie, linezolid and intravenous methylene blue]). Monitor patients closely for signs of SS such as mental status changes (eg, agitation, hallucinations, delirium, coma); autonomic instability (eg, tachycardia, labile blood pressure, diaphoresis); neuromuscular changes (eg, tremor, rigidity, myoclonus); GI symptoms (eg, nausea, vomiting, diarrhea); and/or seizures. Discontinue treatment (and any concomitant serotonergic agent) immediately if signs/symptoms arise. Disease-related concerns:

Pharmacokinetics of imipramine may be altered in patients with chronic alcohol use disorder; increased clearance and a decreased elimination half-life have been reported (Sallee 1990).

Use with caution in patients with a history of cardiovascular disease (including previous MI, stroke, tachycardia, or conduction abnormalities); the risk of conduction abnormalities with this agent is high relative to other antidepressants. In a scientific statement from the American Heart Association, imipramine has been determined to be an agent that may exacerbate underlying myocardial dysfunction (magnitude: moderate) (AHA [Page 2016]). Baseline and periodic assessment of EKG is recommended with use of higher dosages, and should also be considered in elderly patients and/or patients with preexisting cardiovascular disease.

Use with caution in patients with diabetes mellitus; may alter glucose regulation.

Use with caution in patients with hepatic impairment.

May worsen psychosis in some patients or precipitate a shift to mania or hypomania in patients with bipolar disorder. Monotherapy in patients with bipolar disorder should be avoided. Patients presenting with depressive symptoms should be screened for bipolar disorder. Imipramine is not FDA approved for the treatment of bipolar depression.

May cause mild pupillary dilation which in susceptible individuals can lead to an episode of narrow-angle glaucoma. Consider evaluating patients who have not had an iridectomy for narrow-angle glaucoma risk factors.

Use with caution in patients with renal impairment.

Use with caution in patients at risk of seizures, including those with a history of seizures, head trauma, brain damage, alcoholism, or concurrent therapy with medications which may lower seizure threshold. Concurrent drug therapy issues:

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Special populations:

A dose of 2.5 mg/kg/day of imipramine hydrochloride should not be exceeded in childhood. ECG changes of unknown significance have been reported in pediatric patients with doses twice this amount.

Lower doses may be required in geriatric patients due to pharmacokinetic changes.

Imipramine levels may be lower in patients who smoke (Sallee 1990). Dosage form specific issues:

Some formulations may contain tartrazine (FD&C Yellow No. 5) which may cause allergic-type reactions (including bronchial asthma) in susceptible individuals, particularly those who also have aspirin sensitivity. Other warnings/precautions:

Abrupt discontinuation or interruption of antidepressant therapy has been associated with a discontinuation syndrome. Symptoms arising may vary with antidepressant however commonly include nausea, vomiting, diarrhea, headaches, light-headedness, dizziness, diminished appetite, sweating, chills, tremors, paresthesias, fatigue, somnolence, and sleep disturbances (eg, vivid dreams, insomnia). Less common symptoms include electric shock-like sensations, cardiac arrhythmias (more common with tricyclic antidepressants), myalgias, parkinsonism, arthralgias, and balance difficulties. Psychological symptoms may also emerge such as agitation, anxiety, akathisia, panic attacks, irritability, aggressiveness, worsening of mood, dysphoria, mood lability, hyperactivity, mania/hypomania, depersonalization, decreased concentration, slowed thinking, confusion, and memory or concentration difficulties. Greater risks for developing a discontinuation syndrome have been associated with antidepressants with shorter half-lives, longer durations of treatment, and abrupt discontinuation. For antidepressants of short or intermediate half-lives, symptoms may emerge within 2 to 5 days after treatment discontinuation and last 7 to 14 days (APA 2010; Fava 2006; Haddod 2001; Shelton 2001; Warner 2006).

May increase the risks associated with electroconvulsive therapy; consider discontinuing, when possible, prior to ECT treatment.

Recommended by the manufacturer to discontinue prior to elective surgery; risks exist for drug interactions with anesthesia and for cardiac arrhythmias. However, definitive drug interactions have not been widely reported in the literature and continuation of tricyclic antidepressants is generally recommended as long as precautions are taken to reduce the significance of any adverse events that may occur. Norepinephrine should be considered the vasopressor of choice for TCA-related hypotension (Pass 2004). Therapy should not be abruptly discontinued in patients receiving high doses for prolonged periods.