indication

For relief of symptoms in various depressive syndromes, especially endogenous depression. It has also been used to manage chronic peripheral neuropathic pain, as a second line agent for the management of anxiety disorders (e.g. panic disorder, generalized anxiety disorder), and as a second or third line agent in the ADHD management.

pharmacology

Desipramine, a secondary amine tricyclic antidepressant, is structurally related to both the skeletal muscle relaxant cyclobenzaprine and the thioxanthene antipsychotics such as thiothixene. It is the active metabolite of imipramine, a tertiary amine TCA. The acute effects of desipramine include inhibition of noradrenaline re-uptake at noradrenergic nerve endings and inhibition of serotonin (5-hydroxy tryptamine, 5HT) re-uptake at the serotoninergic nerve endings in the central nervous system. Desipramine exhibits greater noradrenergic re-uptake inhibition compared to the tertiary amine TCA imipramine. In addition to inhibiting neurotransmitter re-uptake, desipramine down-regulates beta-adrenergic receptors in the cerebral cortex and sensitizes serotonergic receptors with chronic use. The overall effect is increased serotonergic transmission. Antidepressant effects are typically observed 2 - 4 weeks following the onset of therapy though some patients may require up to 8 weeks of therapy prior to symptom improvement. Patients experiencing more severe depressive episodes may respond quicker than those with mild depressive symptoms.

mechanism of action

Desipramine is a tricyclic antidepressant (TCA) that selectively blocks reuptake of norepinephrine (noradrenaline) from the neuronal synapse. It also inhibits serotonin reuptake, but to a lesser extent compared to tertiary amine TCAs such as imipramine. Inhibition of neurotransmitter reuptake increases stimulation of the post-synaptic neuron. Chronic use of desipramine also leads to down-regulation of beta-adrenergic receptors in the cerebral cortex and sensitization of serotonergic receptors. An overall increase in serotonergic transmission likely confers desipramine its antidepressant effects. Desipramine also possesses minor anticholinergic activity, through its affinity for muscarinic receptors. TCAs are believed to act by restoring normal levels of neurotransmitters via synaptic reuptake inhibition and by increasing serotonergic neurotransmission via serotonergic receptor sensitization in the central nervous system.

toxicity

Male mice: LD50 = 290 mg/kg, female rats: LD50 = 320 mg/kg. Antagonism of the histamine H₁ and α₁ receptors can lead to sedation and hypotension. Antimuscarinic activity confers anticholinergic side effects such as blurred vision, dry mouth, constipation and urine retention may occur. Cardiotoxicity may occur with high doses of desipramine. Cardiovascular side effects in postural hypotension, tachycardia, hypertension, ECG changes and congestive heart failure. Psychotoxic effects include impaired memory and delirium. Induction of hypomanic or manic episodes may occur in patients with a history of bipolar disorder. Withdrawal symptoms include GI disturbances (e.g. nausea, vomiting, abdominal pain, diarrhea), anxiety, insomnia, nervousness, headache and malaise.

biotransformation

Desipramine is extensively metabolized in the liver by CYP2D6 (major) and CYP1A2 (minor) to 2-hydroxydesipramine, an active metabolite. 2-hydroxydesipramine is thought to retain some amine reuptake inhibition and may possess cardiac depressant activity. The 2-hydroxylation metabolic pathway of desipramine is under genetic control.

absorption

Desipramine hydrochloride is rapidly and almost completely absorbed from the gastrointestinal tract. It undergoes extensive first-pass metabolism. Peak plasma concentrations are attained 4 - 6 hours following oral administration.

half life

7-60+ hours; 70% eliminated renally

route of elimination

Desipramine is metabolized in the liver, and approximately 70% is excreted in the urine.

drug interactions

Altretamine: Risk of severe hypotension

Artemether: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Atazanavir: Atazanavir may increase the effect and toxicity of the tricyclic antidepressant, desipramine, by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of desipramine if atazanavir is initiated, discontinued or dose changed.

Butabarbital: Barbiturates like butabarbital may increase the metabolism of tricyclic antidepressants like desipramine. Monitor for decreased therapeutic effects of tricyclic antidepressants if a barbiturate is initiated/dose increased, or increased effects if a barbiturate is discontinued/dose decreased. The tricyclic antidepressant dosage will likely need to be increased during concomitant barbiturate therapy, and reduced upon barbiturate discontinuation.

Butalbital: Barbiturates such as butalbital may increase the metabolism of tricyclic antidepressants such as desipramine. Monitor for decreased therapeutic effects of tricyclic antidepressants if a barbiturate is initiated/dose increased, or increased effects if a barbiturate is discontinued/dose decreased. The tricyclic antidepressant dosage will likely need to be increased during concomitant barbiturate therapy, and reduced upon barbiturate discontinuation.

Carbamazepine: Carbamazepine may decrease the serum concentration of the tricyclic antidepressant, desipramine, by increasing its metabolism. Monitor for changes in the therapeutic and adverse effects of desipramine if carbamazepine is initiated, discontinued or dose changed.

Cimetidine: Cimetidine may increase the effect of the tricyclic antidepressant, desipramine, by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of desipramine if cimetidine is initiated, discontinued or dose changed.

Cisapride: Increased risk of cardiotoxicity and arrhythmias

Clonidine: The tricyclic antidepressant, desipramine, decreases the effect of clonidine.

Desvenlafaxine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Dihydroquinidine barbiturate: Dihydroquinidine barbiturate increases the effect of the tricyclic antidepressant, desipramine.

Dobutamine: The tricyclic antidepressant, desipramine, increases the sympathomimetic effect of dobutamine.

Donepezil: Possible antagonism of action

Dopamine: The tricyclic antidepressant, desipramine, increases the sympathomimetic effect of dopamine.

Duloxetine: Possible increase in the levels of this agent when used with duloxetine

Ephedra: The tricyclic antidepressant, desipramine, increases the sympathomimetic effect of ephedra.

Ephedrine: The tricyclic antidepressant, desipramine, increases the sympathomimetic effect of ephedrine.

Epinephrine: Trimipramine may increase the vasopressor effect of the direct-acting alpha-/beta-agonist, Epinephrine. Avoid combination if possible. Monitor sympathetic response to therapy if used concomitantly.

Fenoterol: The tricyclic antidepressant, desipramine, increases the sympathomimetic effect of fenoterol.

Fluoxetine: The SSRI, fluoxetine, may increase the serum concentration of the tricyclic antidepressant, desipramine, by decreasing its metabolism. Additive modulation of serotonin activity also increases the risk of serotonin syndrome. Monitor for development of serotonin syndrome during concomitant therapy. Monitor for changes in the therapeutic and adverse effects of desipramine if fluoxetine is initiated, discontinued or dose changed.

Fluvoxamine: The SSRI, fluvoxamine, may increase the serum concentration of the tricyclic antidepressant, desipramine, by decreasing its metabolism. Additive modulation of serotonin activity also increases the risk of serotonin syndrome. Monitor for development of serotonin syndrome during concomitant therapy. Monitor for changes in the therapeutic and adverse effects of desipramine if fluvoxamine is initiated, discontinued or dose changed.

Galantamine: Possible antagonism of action

Grepafloxacin: Increased risk of cardiotoxicity and arrhythmias

Guanethidine: The tricyclic antidepressant, desipramine, decreases the effect of guanethidine.

Isocarboxazid: Possibility of severe adverse effects

Isoproterenol: The tricyclic antidepressant, desipramine, increases the sympathomimetic effect of isoproterenol.

Mephentermine: The tricyclic antidepressant, desipramine, increases the sympathomimetic effect of mephentermine.

Metaraminol: The tricyclic antidepressant, desipramine, increases the sympathomimetic effect of metaraminol.

Methoxamine: The tricyclic antidepressant, desipramine, increases the sympathomimetic effect of methoxamine.

Moclobemide: Possible severe adverse reaction with this combination

Norepinephrine: The tricyclic antidepressant, desipramine, increases the sympathomimetic effect of norepinephrine.

Orciprenaline: The tricyclic antidepressant, desipramine, increases the sympathomimetic effect of orciprenaline.

Phenelzine: Possibility of severe adverse effects

Phenylephrine: The tricyclic antidepressant, desipramine, increases the sympathomimetic effect of phenylephrine.

Phenylpropanolamine: The tricyclic antidepressant, desipramine, increases the sympathomimetic effect of phenylpropanolamine.

Pirbuterol: The tricyclic antidepressant, desipramine, increases the sympathomimetic effect of pirbuterol.

Procaterol: The tricyclic antidepressant, desipramine, increases the sympathomimetic effect of procaterol.

Pseudoephedrine: The tricyclic antidepressant, desipramine, increases the sympathomimetic effect of pseudoephedrine.

Quinidine: Additive QTc-prolonging effects may occur. Quinidine may also increase the serum concentration of the tricyclic antidepressant, desipramine, by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of desipramine if quinidine is initiated, discontinued or dose changed. Monitor for the development of torsades de pointes during concomitant therapy.

Quinidine barbiturate: Quinidine barbiturate increases the effect of tricyclic antidepressant, desipramine.

Rasagiline: Possibility of severe adverse effects

Rifabutin: The rifamycin, rifabutin, may decrease the effect of the tricyclic antidepressant, desipramine, by increasing its metabolism. Monitor for changes in the therapeutic and adverse effects of desipramine if rifabutin is initiated, discontinued or dose changed.

Rifampin: The rifamycin, rifampin, may decrease the effect of the tricyclic antidepressant, desipramine, by increasing its metabolism. Monitor for changes in the therapeutic and adverse effects of desipramine if rifampin is initiated, discontinued or dose changed.

Ritonavir: Ritonavir may increase the effect and toxicity of the tricyclic antidepressant, desipramine, by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of desipramine if ritonavir if initiated, discontinued or dose changed.

Rivastigmine: Possible antagonism of action

Salbutamol: The tricyclic antidepressant, desipramine, increases the sympathomimetic effect of salbutamol.

Sibutramine: Increased risk of CNS adverse effects

Sparfloxacin: Increased risk of cardiotoxicity and arrhythmias

Tacrine: The therapeutic effects of the central acetylcholinesterase inhibitor, Tacrine, and/or the anticholinergic, Desipramine, may be reduced due to antagonism. The interaction may be beneficial when the anticholinergic action is a side effect. Monitor for decreased efficacy of both agents.

Tacrolimus: Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.

Tamoxifen: Desipramine may decrease the therapeutic effect of Tamoxifen by decreasing the production of active metabolites. Consider alternate therapy.

Tamsulosin: Desipramine, a CYP3A4/2D6 inhibitor, may decrease the metabolism and clearance of Tamsulosin, a CYP3A4/2D6 substrate. Monitor for changes in therapeutic/adverse effects of Tamsulosin if Desipramine is initiated, discontinued, or dose changed.

Terbinafine: Terbinafine may increase the effect and toxicity of the tricyclic antidepressant, desipramine, by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of desipramine if terbinafine is initiated, discontinued or dose changed.

Terbutaline: The tricyclic antidepressant, desipramine, increases the sympathomimetic effect of terbutaline.

Terfenadine: Increased risk of cardiotoxicity and arrhythmias

Thiothixene: May cause additive QTc-prolonging effects. Increased risk of ventricular arrhythmias. Consider alternate therapy. Thorough risk:benefit assessment is required prior to co-administration.

Tipranavir: Tipranavir, co-administered with Ritonavir, may increase the concentration of Desipramine. Monitor Desipramine concentration and efficacy/toxicity and adjust dose as required.

Tolterodine: Desipramine may decrease the metabolism and clearance of Tolterodine. Adjust Tolterodine dose and monitor for efficacy and toxicity.

Toremifene: Additive QTc-prolongation may occur, increasing the risk of serious ventricular arrhythmias. Consider alternate therapy. A thorough risk:benefit assessment is required prior to co-administration.

Tramadol: Tramadol increases the risk of serotonin syndrome and seizures. Desipramine may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. Desipramine may decrease the effect of Tramadol by decreasing active metabolite production.

Tranylcypromine: Increased risk of serotonin syndrome. Concomitant therapy should be avoided. A significant washout period, dependent on the half-lives of the agents, should be employed between therapies.

Trazodone: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Trimipramine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome. Additive QTc-prolongation may also occur, increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.

Triprolidine: Triprolidine and Desipramine, two anticholinergics, may cause additive anticholinergic effects and enhance their adverse/toxic effects. Additive CNS depressant effects may also occur. Monitor for enhanced anticholinergic and CNS depressant effects.

Trospium: Trospium and Desipramine, two anticholinergics, may cause additive anticholinergic effects and enhanced adverse/toxic effects. Monitor for enhanced anticholinergic effects.

Venlafaxine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Vilazodone: Monitor for toxic effects of tricyclic antidepressants if a selective serotonin reuptake inhibitor (SSRI) is initiated or the dose is increased. The influence of the SSRI may take several days or weeks to be fully realized or resolved.

Voriconazole: Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).

Vorinostat: Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).

Ziprasidone: Additive QTc-prolonging effects may increase the risk of severe arrhythmias. Concomitant therapy is contraindicated.

Zolmitriptan: Use of two serotonin modulators, such as zolmitriptan and desipramine, increases the risk of serotonin syndrome. Consider alternate therapy or monitor for serotonin syndrome during concomitant therapy.

Zuclopenthixol: Additive QTc prolongation may occur. Consider alternate therapy or use caution and monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).