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Psychopharmacology book

Imipramine (TOFRANIL)

Imipramine (TOFRANIL)

In 1957 imipramine (Tofranil) was released to the US market as the first antidepressant. It was widely prescribed prior to the arrival of better tolerated antidepressants. It is still prescribed for refractory depression.

Impramine (Tofranil) by Dr Jason Cafer MD

Imipramine was originally synthesized in 1951 by tweaking the molecule of the antipsychotic chlorpromazine (Thorazine). At the time, these chemicals were classified as antihistamines. The antipsychotic effect of Thorazine was discovered in 1952. Imipramine was then tested as an antipsychotic but was ineffective for psychosis. Serendipitously, imipramine was found to relieve severe depression. 


Imipramine is an example of a “dirty” chemical, i.e., it affects many neurotransmitter systems indiscriminately.  It highly anticholinergic. Many patients report lightheadedness related to antagonism of alpha-1 adrenergic receptors, which causes orthostatic hypotension. Imipramine is a very poor choice for elderly patients who are at risk for falls. 

Imipramine Tofranil mnemonic interactions and indications by Dr Jason Cafer MD

Imipramine is considered a powerful antidepressant, more likely than others to lead to “switching” to mania when used for bipolar depression. Navarro et al (2019) found that 72% of nonresponders to venlafaxine (Effexor) showed remission of depression when changed to imipramine. By comparison, remission rate was only 39% when mirtazapine (Remeron) was added to venlafaxine. In other words, imipramine was shown to outperform “California Rocket Fuel” (famed combination of mirtazapine and venlafaxine).


Imipramine and clomipramine are the TCAs established as effective for panic disorder. 


Imipramine was used to treat nocturnal enuresis because it shortens the duration of deep sleep, when bedwetting occurs. Other TCAs can be effective for enuresis, but imipramine is the only psychotropic medication FDA-approved for this indication. The other medication approved for enuresis is desmopressin (DDAVP), an antidiuretic derived from vasopressin.


The liver converts imipramine into desipramine (desmethyl-imipramine) as a metabolite. Desipramine (Norpramin) is a “cleaner” drug, affecting fewer neurotransmitter systems and causing fewer side effects. In terms of tolerability, “desipramine is more desirable than imipramine”.


Dosing: Dosing for imipramine is the same as for amitriptyline. For depression start at 10 or 25 mg HS and titrate slowly due to sedative effects. The usual maintenance dose for depression is 50–150 mg HS. Maximum is 300 mg HS (100 mg max for elderly patients); Taper gradually to stop. Therapeutic serum level is 150–300 ng/mL of combined imipramine plus desipramine.

See Tricyclic antidepressants (TCAs)

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