Imipramine: Wikis


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Systematic (IUPAC) name
3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)- N,N-dimethylpropan-1-amine
CAS number 50-49-7
ATC code N06AA02
PubChem 3696
DrugBank APRD00672
ChemSpider 3568
Chemical data
Formula C 19H24N2  
Mol. mass 280.407
Pharmacokinetic data
Bioavailability  ?
Metabolism Hepatic
Main active metabolite desipramine
Half life 11-25 hours
Excretion Renal
Therapeutic considerations
Pregnancy cat. D(US)
Known risk of damage to fetus.
Legal status Prescription only
Routes Oral
 Yes check.svgY(what is this?)  (verify)

Imipramine (sold as Antideprin, Deprimin, Deprinol, Depsonil, Dynaprin, Eupramin, Imipramil, Irmin, Janimine, Melipramin, Surplix, Tofranil) is an antidepressant medication, a tricyclic antidepressant of the dibenzazepine group. Imipramine is mainly used in the treatment of major depression and enuresis (inability to control urination).

It has also been evaluated for use in panic disorder.[1]



Imipramine was, in the late 1950s, the first tricyclic antidepressant to be developed (by Ciba-Geigy). It was first tried against psychotic disorders, such as schizophrenia, but proved insufficient. During the clinical studies, its antidepressant qualities were unsurpassed by other antidepressants. To this day, Imipramine is often considered the "gold standard" antidepressant, as its ability to lift the most severe depressive episodes is unsurpassed. It is not surprising, therefore, that Imipramine is also known to cause a high rate of manic and hypomanic reactions, especially in patients with preexisting bipolar disease. It is estimated that up to 25% of such patients maintained on Imipramine will switch into mania or hypomania.[2 ] Such powerful antidepressant properties have made it favorable in the treatment of treatment-resistant depression.

At the advent of SSRIs, its sometimes intolerable side-effect profile became less tolerable. Therefore, it became extensively used as a standard antidepressant and later served as a prototypical drug for the development of the later-released tricyclics. It is not as commonly used today, but is sometimes used to treat major depression as a second-line treatment. It has also seen limited use in the treatment of migraines, ADD, and post concussive syndrome. Imipramine has additional indications for the treatment of panic attacks, chronic pain, and Kleine-Levin syndrome. In pediatric patients, it is relatively frequently used to treat pavor nocturnus and nocturnal enuresis.

Mechanisms Of Action

Imipramine, a tertiary amine, affects numerous neurotransmitter systems known to be involved in the etiology of depression, anxiety , ADD/ADHD, enuresis and numerous other mental and physical conditions. Imipramine is similar in structure to some muscle relaxants, and has a significant analgesic effect and, thus, is very useful in some pain conditions.

The mechanisms of Imipramine's medicinal action include, but are not limited to, effects on: norepinephrine, serotonin, dopamine, epinephrine, sigma receptor, enkephalinase, histamine, muscarine, and acetylcholine. Imipramine has been shown to interact with opioid systems in the central nervous system, possibly explaining some of its pain-relieving properties. [3] It is also becoming apparent that at least some of Imipramine's effects are epigenetic and related to its promotion of histone acetylation of the BDNF promotor in the hippocampus and also downregulation of histone deacetylase (HDAC5).[4]

Effects on:

Norepinephrine (NE) Reuptake inhibition (strong).

Serotonin (SE) Reuptake inhibition (moderate to strong). The reuptake inhibition is almost comparable but still less than Imipramine's potency of reuptake inhibition on norepinephrine. Stronger SERT inhibition than most other tricyclic antidepressants with the exception of Clomipramine, making it more akin to the SSRI class of antidepressants (e.g., Prozac (fluoxetine), Zoloft (sertraline)) than its metabolite desipramine, which has almost purely noradrenergic effects.

Acetylcholine (ACh) Imipramine is an anticholinergic. Thus, it is prescribed with caution to the elderly and with extreme caution to those with pyschosis, as the general brain activity enhancement in combination with the "dementing" effects of anticholinergics increases the potential of Imipramine to cause hallucinations, confusion and delirium in this population. Imipramine is an antagonist at M2 muscarinic acetylcholine receptors (see external links). The blockade of cholinergic (muscarine) receptors is known to cause euphoria, potentially contributing to the mood lifting effects of Imipramine as well. Antimuscarinic effect is also responsible for rapid heart rate (tachycardia).

Epinephrine Imipramine antagonizes adreno-receptors (II), thus sometimes causing increased heart rate (contributed to by other effects as well), orthostatic hypotension, and a general decrease in the responsiveness of the central nervous system (hence, a contribution to its potent anti-anxiety properties).

Dopamine Reuptake and release at D1 and D2 receptors, similar to, but less potent than, psychostimulants, dopamine agonists, and atypical antidepressant buproprion on dopaminergic mechanisms (increase in release and blockade of reuptake inhibition). While this effect is much less than the primary effects on NE, SE and ACe, it is nonetheless significant and is partially responsible for the therapeutic benefits of treatment with Imipramine. Enhancement of brain dopamine activity has been implicated in Imipramine's ability to stimulate motor activity and prolong time spent in escape in mice. Regarding dopamine uptake, imipramine is far less potent than most other antidepressants (for example, it is 1/20 the potency of amitryptiline and paroxetine, see references).

Sigma receptor and Enkephalinase Activity on sigma receptors (sigma ligands) is present, but it is very low (Ki of 520 nM on sigma receptors, see references) and it is about half the power of amitryptiline (300 nM).

Histamine Imipramine is an antagonist at histamine H1 receptors. This contributes to the acute sedative effect that it has in most people. In turn, its anti-histaminergic and general calming effects take place immediately, and, thus, Imiparmine is sometimes prescribed as a sleep aid in low doses.

BDNF Brain derived neurotrophic factor (BDNF) is implicated in neurogenesis in the hippocampus, and studies suggest that depressed patients have decreased levels of BDNF and reduced hippocampal neurogenesis. It is not clear how neurogenesis restores mood, as ablation of hippocampal neurogenesis in murine models do not show anxiety related or depression related behaviours. Chronic Imipramine administration results in increased histone acetylation (which is associated with transcriptional activation and decondensed chromatin) at the hippocampal BDNF promotor, and also reduced expression of hippocampal histone deacetylase (hdac5).[5]

Comparison with other antidepressants

The potency (affinity) of imipramine and other antidepressant on various transporters and receptors are summarized below. Data are from "Pharmacology of antidepressant", Mayo Clin Proc, May 2001, Vol 76.[6]

Potency (affinity) data are expressed as the inverse of equilibrium dissocation constant multiplied by a factor of 10^-7. So, the higher the number, the higher the blocking power.

Drug NE Transporter SE Transporter DE transporter alpha1 blockade D2 blockade H1 blockade muscarinic blockade 5HT2 blockade
imipramine 2.7 70 0.012 1.5 0.05 9.1 1.1 1.2
desipramine (also an imipramine metabolite) 128 5.7 0.024 0.77 0.03 0.91 0.5 0.38
amitriptyline 2.9 23 0.023 3.7 0.1 91 5.6 3.4
clomipramine 2.7 360 0.045 2.6 0.53 3.2 2.7 3.7
paroxetine 2.5 800 0.2 0.025 0.003 0.03 0.93 0.005
citalopram 0.035 98 0.0038 0.053 0 0.21 0.045 0.34


Imipramine is converted to desipramine, another TCA, in the body.

Contraindications and precautions

(See Tricyclic antidepressants)


After taking the medicine this drug may cause some side-effects in some patients, particularly with the first few doses.

Allergy: isolated cases of pneumonitis (fever, chills, cough, difficulty with breathing, unusual weight loss, feeling sick, puffy, swollen face, tongue or body) have been reported. These reactions may be severe, causing shortness of breath, swelling, shock and collapse.

Isolated changes in blood cells.

Arrhythmias: irregular heart rhythms.

Weight gain has been reported frequently. Disturbances in sexual function have been reported occasionally. Isolated cases of enlarged mammary glands, production or over-production of breast milk, increased or decreased blood sugar levels and weight loss have been reported. Low levels of salt in the blood have been reported, usually in elderly patients.

Tremor has been reported frequently. Headache, confusion, orthostatic hypotension (resulting in dizziness upon standing), numbness/tingling, agitation, anxiety, restlessness, mood swings, exaggerated behaviour, delusions and hallucinations have been reported occasionally and are more common in the elderly or in patients on high doses. Aggressiveness, weakness, lack of co-ordination, sudden muscle spasms, difficulty speaking have been reported in isolated cases.

Imipramine also enhances the CNS effects of both stimulants and alcohol, and blocks the parasympathomimetic effects of stimulants while enhancing the cortical excitation. This can be dangerous in some cases and result in seizures and coma.

Ringing or buzzing in the ears.

Feeling or being sick and loss of appetite have been reported occasionally. Isolated cases of tongue lesions and inflammation of the mucus membranes in the mouth have been reported. Extreme dry mouth or "cotton mouth" has been reported. Mild to severe constipation has also been reported.

Changes in liver function have been reported occasionally. Hepatitis and jaundice (yellowing of the skin and/or whites of the eyes) have been reported in isolated cases.

Allergic reactions such as an itchy skin rash have been reported occasionally. Isolated cases of swelling, sensitivity to the sun or sun lamps, hair loss, small purple red spots and itching have been reported.

If the medicine is stopped too quickly, there is the possibility the user may suffer from feeling or being sick, stomach pains, diarrhea, headache, sleeplessness, nervousness, anxiety, irritability and increased sweating.


  • Hospitalized patients: starting with 3 times 25 mg, increasing to 125 mg. Up to 300 mg may be given in resistant cases. After remission dose is often reduced to 50 to 100 mg daily.
  • Ambulatory patients: starting with 25 to 75 mg daily, increasing up to a maximum of 200 mg daily, after remission dose is often reduced to 50–100 mg daily.
  • Pediatric patients: starting with 10 mg daily the dose is adjusted according to the severity of the symptoms to be treated, the side-effects encountered and the weight of the patient.


The symptoms and the treatment of an overdose are largely the same as for the other tricyclic antidepressants. Cardinal symptoms are cardiac (tachycardia, widened QRS complex) and neurological disturbances. Any ingestion by children should be considered as serious and potentially fatal.


  1. ^ Lepola U, Arató M, Zhu Y, Austin C (June 2003). "Sertraline versus imipramine treatment of comorbid panic disorder and major depressive disorder". J Clin Psychiatry 64 (6): 654–62. PMID 12823079.  
  2. ^ Bottlender R, Rudolf D, Strauss A, Möller HJ (1998). "Antidepressant-associated maniform states in acute treatment of patients with bipolar-I depression". European Archives of Psychiatry and Clinical Neuroscience 248 (6): 296–300. doi:10.1007/s004060050053. PMID 9928908.  
  3. ^ Effects of imipramine administration on mu-opioid receptor immunostaining in the rat forebrain. de Gandarias JM, Echevarria E, Acebes I, Silio M, Casis L. 1: Arzneimittelforschung. 1998 Jul;48(7):717-9
  4. ^ Tsankova NM, Berton O, Renthal W, Kumar A, Neve RL, Nestler EJ (April 2006). "Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action". Nature Neuroscience 9 (4): 519–25. doi:10.1038/nn1659. PMID 16501568.  
  5. ^ Krishnan V, Nestler EJ (October 2008). "The molecular neurobiology of depression". Nature 455 (7215): 894–902. doi:10.1038/nature07455. PMID 18923511.  
  6. ^ Richelson E (May 2001). "Pharmacology of antidepressants". Mayo Clinic Proceedings. Mayo Clinic 76 (5): 511–27. doi:10.4065/76.5.511. PMID 11357798.  

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