Desipramine


Article Author:
Jasdave Maan


Article Editor:
Abdolreza Saadabadi


Editors In Chief:
Melissa Max
Danyae Lee
Manouchkathe Cassagnol


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Orawan Chaigasame
Carrie Smith
Abdul Waheed
Frank Smeeks
Kristina Soman-Faulkner
Benjamin Eovaldi
Radia Jamil
Sobhan Daneshfar
Saad Nazir
William Gossman
Pritesh Sheth
Hassam Zulfiqar
Navid Mahabadi
Steve Bhimji
John Shell
Matthew Varacallo
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Hajira Basit
Phillip Hynes


Updated:
5/6/2019 9:31:52 PM

Indications

Desipramine is a secondary amine tricyclic antidepressant that is FDA approved for the treatment of depression. It is not considered the first line for depression due to the several adverse effects of this drug. This drug has been used off-label to treat bulimia nervosa, irritable bowel syndrome, neuropathic pain, overactive bladder, post-herpetic neuralgia, and ADHD. Efficacy of desipramine can be established within the first 2 weeks of treatment of bulimia nervosa patients. This was established by a study of 77 patients plotted on a receiver operating character curve examining the relationship between time and symptom reduction. Alleviation of symptoms in irritable bowel syndrome and neuropathic pain is accomplished by the antinociceptive properties of Desipramine. Desipramine has been shown to have therapeutic antinociceptive benefits most likely via its influence of norepinephrine. In addition to patients with simple overactive bladder, desipramine was found useful in patients with complex overactive bladder caused by pelvic radiation and overactive bladder with pain. Desipramine has been established as one of the first-line drugs in treating postherpetic neuralgia, however, due to its toxic profile physicians are often inclined to use second-line medications such as gabapentin. Desipramine has shown mild effectiveness in the treatment of ADHD.[1][2][3]

Mechanism of Action

Currently, the most widely accepted theory of desipramine’s mechanism of action is that it blocks the reuptake of norepinephrine and serotonin in the presynaptic neuronal membrane. Secondary amine tricycle antidepressants such as desipramine have been proposed to have greater norepinephrine blockade compared to that of tertiary amine tricyclic antidepressants, which have greater blockade at serotonin receptors. Reuptake blockade increases the available amount of neurotransmitter in the synapse. Antinociceptive effects of desipramine are believed to be achieved via manipulation of norepinephrine. In addition to these mechanisms, desipramine appears to downregulate beta-adrenergic receptors and serotonin receptors. It also proposed to have alpha-1 blocking, antihistamine, and anticholinergic effects as well.[4][5][6][7]

Administration

Desipramine is administered orally and comes in tablets of 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, and 150 mg.  For depression, the initial dosage should be started at 25 mg to 50 mg daily and increased to 100 mg to 200 mg. The maximum dose is 300 mg a day, usually in an inpatient or hospital setting to monitor for possible adverse effects.

Adverse Effects

Desipramine has a wide toxic profile including an increased risk for suicide, orthostatic hypotension, cardiac abnormalities, seizures, ocular crisis, and fractures. A short-term study showed a significantly increased risk of suicide in children, adolescents and young adults ages 24 and younger. This is one of the most important adverse effects to consider when prescribing desipramine. Orthostatic hypotension, likely due to blockade of alpha one receptors, is a common reason for discontinuation of this drug. Cardiovascular side effects such as heart block, arrhythmias, and sudden death have been reported with this drug. Screening for conduction disease with special attention to QT interval and the history of cardiac disease within the family is highly recommended before the prescription.[8]

Anticholinergic properties lead to side effects such as blurred visions, constipation tachycardia, confusions, dry mouth, urinary retention, delirium, and the ocular crisis in patients with narrow-angle glaucoma. A recent study shows an increased risk for dementia due to the anticholinergic properties of this drug and that this risk is additive with other drugs that have anticholinergic properties. There is an increased risk of osteoporotic fracture with desipramine and all other antidepressants. Osteoblasts, osteocytes, and osteoclasts all have serotonin receptors, indicating a relationship between the neuroendocrine system and bone. Seizure threshold seems to decrease.

Other side effects include acute hepatitis, bone marrow toxicity, sexual dysfunction, seizures, sedation, tremors, and diaphoresis. Diaphoresis has been proposed to be caused by noradrenergic receptor manipulation. With sexual dysfunction, there have been reports of impaired arousal and orgasms likely due to serotonergic effects. Although less sedating compared to other tricyclics, desipramine’s antihistaminic properties lead to sedation. Relative to the drug class of tricyclic antidepressants, desipramine is the least likely to cause the side effects listed.

Contraindications

This medication is contraindicated in patients that have used monoamine oxidase inhibitors within the last 14 days to avoid serotonin syndrome. Such contraindicated drugs include tranylcypromine, phenelzine, isocarboxazid, selegiline, intravenous methylene blue, and linezolid. Desipramine is contraindicated in the acute recovery period following myocardial infarction. This drug should not be used in those who have had prior hypersensitivity to the drug. Having cross-sensitivity between this drug and other dibenzazepine drugs is possible.

Monitoring

The optimal range has not been established in this drug, but some studies site the range is between 50ng/ml -300ng/ml. 115ng/ml was shown to be an important median in another research study showing efficacy in elderly melancholic patients. Patients below 115ng/ml tended to not respond to treatment. A similar conclusion was reached in younger patient populations with the same median. Treatment with this drug requires a minimum of 2-3 weeks to see the full effect.  Desipramine is metabolized in the liver and should be monitored for possible under-metabolism or over-metabolism with other drugs that metabolize in the liver such as cimetidine. Another important point is to watch for worsening of depression or the emergence of suicidal ideas during the initial period of taking this medication in patients under 24. It is generally believed that antidepressants will precipitate a manic or mixed episode in a bipolar patient. Extreme precautions should be taken in a patient with cardiovascular disease due to conduction defects, tachycardia, stroke, and acute myocardial infarction. Patient with a family history of sudden death, cardiac dysrhythmia, or cardiac conduction distances should be intensely monitored. Widening of QRS complex greater than 100 msec is a common indicator of toxicity. Renal function should be assessed because Desipramine is primarily exerted in the urine. Although bone marrow suppression and acute hepatitis are adverse side effects of this drug, there is no need to monitor these situations in the absence of history or symptoms. Antidepressant discontinuation syndrome may occur if you abruptly discontinue desipramine. This syndrome consists of mild flu-like symptoms that can last up to 2 weeks. Additional symptoms include insomnia, nausea, dizziness, gastrointestinal complaints, imbalance, sensory disturbances, and hyperarousal.  These symptoms can emerge hours to days after discontinuing this drug and are immediately relieved by the reestablishment of antidepressant therapy. Suspicion of this syndrome should lead to questioning of patients medication regime or of any scheduling where they skip days of treatment. To avoid antidepressant discontinuation syndrome, Desipramine should be slowly tapered over a period of weeks to months.

Toxicity

Desipramine has resulted in a higher death rate compared to other tricyclic antidepressants. An overdose of this drug results in cardiac dysrhythmia, critical hypotension, convulsions, becoming comatose, convulsions, hyperactive reflexes, stupid, drowsiness, hypothermia, and confusion. Serotonin syndrome is acquired to due excessive serotonin often causes but a mixture of antidepressant and MAOIs. Signs and symptoms of serotonin syndrome include hyperthermia, agitation, dilated pupils, dilated pupils, tremor, akathisia, muscle rigidity, increased bowel sounds, flushed skin, and diaphoresis. First line treatment for acute toxicity is supportive care, serum alkalization, ECG, and gastric decontamination. Observation must be for at least 6 hours for unexplained syncope shortness of breath palpitations and chest pain. Gastrointestinal decontamination should be initiated via activated charcoal as soon as possible. Emesis is contraindicated with the toxicity of desipramine. In patients with serotonin syndrome, management consists of supportive care and serotonin antagonists.

Enhancing Healthcare Team Outcomes

Desipramine was once widely used to manage several mental health disorders. However, because of its toxicity and adverse effects, it is no longer used much today. But any healthcare professional who prescribes it must be fully aware of its side effect profile. Patients should be educated on the side effects and the need to store the drug away from children. 


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Desipramine - Questions

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Which drug has been associated with sudden cardiac death?



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Which of the following antidepressants is more selective in blocking the reuptake of norepinephrine as compared with serotonin?



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Desipramine is classified as which of the following?



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A 77-year-old woman comes in for a follow up on her labs. She has a past medical history that is significant for shingles, depression, and hypothyroidism. Today she complains of having blurry vision, decreased memory, and a dry mouth. She is concerned that her diet is causing her memory loss. She has been eating more fast food as of late and drinking two beers a week. Her recent labs show her TSH is 3.0 mIU/L and her hemoglobin A1c is 5.0%. She is currently on desipramine, levothyroxine, and multivitamin supplements. Which of the following is an appropriate response by the provider?



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A 14-year-old child comes in for a 2 week follow up on his depression. He has been difficulty sleeping, concentrating, and controlling his appetite. He complains he is still often sad and has not gone to school for 2 days. He was recently started on 25 mg of desipramine. He does not complain of any shortness of breath, chest pain, or dizziness. Which of the following is the most important initial assessment on this visit?



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A 45-year-old male comes in for refractory depression. He has tried several medications that have failed to improve his depression. During this visit, it is decided to start him on desipramine. Which of the following is a contraindication to this medication?



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Desipramine - References

References

Desipramine 2006;     [PubMed]
Osland ST,Steeves TD,Pringsheim T, Pharmacological treatment for attention deficit hyperactivity disorder (ADHD) in children with comorbid tic disorders. The Cochrane database of systematic reviews. 2018 Jun 26;     [PubMed]
Agabio R,Trogu E,Pani PP, Antidepressants for the treatment of people with co-occurring depression and alcohol dependence. The Cochrane database of systematic reviews. 2018 Apr 24;     [PubMed]
Riediger C,Schuster T,Barlinn K,Maier S,Weitz J,Siepmann T, Adverse Effects of Antidepressants for Chronic Pain: A Systematic Review and Meta-analysis. Frontiers in neurology. 2017;     [PubMed]
Euwema MS,Swanson TJ, Deadly Single Dose Agents 2018 Jan;     [PubMed]
Dean L, Amitriptyline Therapy and {i}CYP2D6{/i} and {i}CYP2C19{/i} Genotype 2012;     [PubMed]
Dean L, Imipramine Therapy and {i}CYP2D6{/i} and {i}CYP2C19{/i} Genotype 2012;     [PubMed]
Caldwell PH,Sureshkumar P,Wong WC, Tricyclic and related drugs for nocturnal enuresis in children. The Cochrane database of systematic reviews. 2016 Jan 20;     [PubMed]

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