CLOMIPRAMINE

brands

Class

• Neuroscience-based Nomenclature: serotonin reuptake inhibitor (S-RI)
• Tricyclic antidepressant (TCA)
• Parent drug is a potent serotonin reuptake inhibitor
• Active metabolite is a potent norepinephrine reuptake inhibitor

CLOMIPRAMINE commonly prescribed for

(Bold for FDA approved)

How CLOMIPRAMINE works

• Boosts neurotransmitters serotonin and norepinephrine

• Blocks serotonin reuptake pump (serotonin transporter), presumably increasing serotonergic neurotransmission

• Blocks norepinephrine reuptake pump (norepinephrine transporter), presumably increasing noradrenergic neurotransmission

• Presumably desensitizes both serotonin 1A receptors and beta adrenergic receptors

• Since dopamine is inactivated by norepinephrine reuptake in frontal cortex, which largely lacks dopamine transporters, clomipramine can increase dopamine neurotransmission in this part of the brain

How long until CLOMIPRAMINE works

• May have immediate effects in treating insomnia or anxiety

• Onset of therapeutic actions in depression usually not immediate, but often delayed 2 to 4 weeks

• Onset of therapeutic action in OCD can be delayed 6 to 12 weeks

• If it is not working for depression within 6 to 8 weeks, it may require a dosage increase or it may not work at all

• If it is not working for OCD within 12 weeks, it may not work at all

• May continue to work for many years to prevent relapse of symptoms

Notable Side Effects

• Blurred vision, constipation, urinary retention, increased appetite, dry mouth, nausea, diarrhea, heartburn, unusual taste in mouth, weight gain

• Fatigue, weakness, dizziness, sedation, headache, anxiety, nervousness, restlessness

• Sexual dysfunction, sweating

Life Threatening Side Effects

• Paralytic ileus, hyperthermia (TCAs + anticholinergic agents)

• Lowered seizure threshold and rare seizures

• Orthostatic hypotension, sudden death, arrhythmias, tachycardia

• QTc prolongation

• Hepatic failure, drug-induced parkinsonism

• Increased intraocular pressure

• Rare induction of mania

• Rare activation of suicidal ideation and behavior (suicidality) (short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo beyond age 24)

weight gain

common

sedation

common

What to do about CLOMIPRAMINE side effects

• Wait

• Wait

• Wait

• Lower the dose

• Switch to an SSRI or newer antidepressant

usual dosage range

• 100–200 mg/day

Dosage Forms

• Capsule 25 mg, 50 mg, 75 mg

long term use

• Limited data but appears to be efficacious and safe long-term

habit forming

• No

Renal Impairment

• Use with caution

Hepatic Impairment

• Use with caution

Cardiac Impairment

• Baseline ECG is recommended

• TCAs have been reported to cause arrhythmias, prolongation of conduction time, orthostatic hypotension, sinus tachycardia, and heart failure, especially in the diseased heart

• Myocardial infarction and stroke have been reported with TCAs

• TCAs produce QTc prolongation, which may be enhanced by the existence of bradycardia, hypokalemia, congenital or acquired long QTc interval, which should be evaluated prior to administering clomipramine

• Use with caution if treating concomitantly with a medication likely to produce prolonged bradycardia, hypokalemia, slowing of intracardiac conduction, or prolongation of the QTc interval

• Avoid TCAs in patients with a known history of QTc prolongation, recent acute myocardial infarction, and uncompensated heart failure

• TCAs may cause a sustained increase in heart rate in patients with ischemic heart disease and may worsen (decrease) heart rate variability, an independent risk of mortality in cardiac populations

• Since SSRIs may improve (increase) heart rate variability in patients following a myocardial infarct and may improve survival as well as mood in patients with acute angina or following a myocardial infarction, these are more appropriate agents for cardiac population than tricyclic/tetracyclic antidepressants

• Risk/benefit ratio may not justify use of TCAs in cardiac impairment

Elderly

• Baseline ECG is recommended for patients over age 50

• May be more sensitive to anticholinergic, cardiovascular, hypotensive, and sedative effects

• Dose may need to be lower than usual adult dose, at least initially

• Reduction in the risk of suicidality with antidepressants compared to placebo in adults age 65 and older

Children and Adolescents

• Carefully weigh the risks and benefits of pharmacological treatment against the risks and benefits of nontreatment with antidepressants and make sure to document this in the patient’s chart

• Monitor patients face-to-face regularly, particularly during the first several weeks of treatment

• Use with caution, observing for activation of known or unknown bipolar disorder and/ or suicidal ideation, and inform parents or guardians of this risk so they can help observe child or adolescent patients

• Not recommended for use in children under age 10

• Several studies show lack of efficacy of TCAs for depression

• May be used to treat enuresis or hyperactive/impulsive behaviors

• Effective for OCD in children

• Some cases of sudden death have occurred in children taking TCAs

• Dose in children/adolescents should be titrated to a maximum of 100 mg/day or 3 mg/kg per day after 2 weeks, after which dose can then be titrated up to a maximum of 200 mg/day or 3 mg/kg per day

Pregnancy

• Effective June 30, 2015, the FDA requires changes to the content and format of pregnancy and lactation information in prescription drug labels, including the elimination of the pregnancy letter categories; the Pregnancy and Lactation Labeling Rule (PLLR or final rule) applies only to prescription drugs and will be phased in gradually for drugs approved on or after June 30, 2001

• Controlled studies have not been conducted in pregnant women

• Clomipramine crosses the placenta

• Adverse effects have been reported in infants whose mothers took a TCA (lethargy, withdrawal symptoms, fetal malformations)

• Must weigh the risk of treatment (first trimester fetal development, third trimester newborn delivery) to the child against the risk of no treatment (recurrence of depression, worsening of OCD, maternal health, infant bonding) to the mother and child

• For many patients this may mean continuing treatment during pregnancy

Breast Feeding

• Some drug is found in mother’s breast milk

• Recommended either to discontinue drug or bottle feed

• Immediate postpartum period is a high-risk time for depression and worsening of OCD, especially in women who have had prior depressive episodes or OCD symptoms, so drug may need to be reinstituted late in the third trimester or shortly after childbirth to prevent a recurrence or exacerbation during the postpartum period

• Must weigh benefits of breast feeding with risks and benefits of antidepressant treatment versus nontreatment to both the infant and the mother

• For many patients this may mean continuing treatment during breast feeding