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Desipramine
Desipramine
Desipramine
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Desipramine
Skeletal formula of desipramine
Ball-and-stick model of the desipramine molecule
Clinical data
Trade namesNorpramin, Pertofrane, others
Other namesDesmethylimipramine; Norimipramine; EX-4355; G-35020; JB-8181; NSC-114901[1][2][3]
AHFS/Drugs.comMonograph
MedlinePlusa682387
Routes of
administration		Oral, intramuscular injection
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability60–70%[5]
Protein binding91%[5]
MetabolismLiver (CYP2D6)[6]
Elimination half-life12–30 hours[5]
ExcretionUrine (70%), feces[5]
Identifiers
  • 3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N-methylpropan-1-amine
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.000.037 Edit this at Wikidata
Chemical and physical data
FormulaC18H22N2
Molar mass266.388 g·mol−1
3D model (JSmol)
  • c1cc3c(cc1)CCc2c(cccc2)N3CCCNC
  • InChI=1S/C18H22N2/c1-19-13-6-14-20-17-9-4-2-7-15(17)11-12-16-8-3-5-10-18(16)20/h2-5,7-10,19H,6,11-14H2,1H3 checkY
  • Key:HCYAFALTSJYZDH-UHFFFAOYSA-N checkY
  (verify)

Desipramine, sold under the brand name Norpramin among others, is a tricyclic antidepressant (TCA) used in the treatment of depression.[7] It acts as a relatively selective norepinephrine reuptake inhibitor, though it does also have other activities such as weak serotonin reuptake inhibitory, α1-blocking, antihistamine, and anticholinergic effects. The drug has not been considered a first-line treatment for depression since the introduction of selective serotonin reuptake inhibitor (SSRI) antidepressants, which have fewer side effects and are safer in overdose.

Medical uses

[edit]

Desipramine is primarily used for the treatment of depression.[7] It may also be useful to treat symptoms of attention-deficit hyperactivity disorder (ADHD).[8] Evidence of benefit is only in the short term, and with concerns of side effects its overall usefulness is not clear.[9] Desipramine at very low doses is also used to help reduce the pain associated with functional dyspepsia.[10] It has also been tried, albeit with little evidence of effectiveness, in the treatment of cocaine dependence.[11] Evidence for usefulness in neuropathic pain is also poor.[12]

Side effects

[edit]

Desipramine tends to be less sedating than other TCAs and tends to produce fewer anticholinergic effects such as dry mouth, constipation, urinary retention, blurred vision, and cognitive or memory impairments.[13]

Overdose

[edit]
Main article: Tricyclic antidepressant overdose

Desipramine is particularly toxic in cases of overdose, compared to other antidepressants.[14] Any overdose or suspected overdose of desipramine is considered to be a medical emergency and can result in death without prompt medical intervention.

Pharmacology

[edit]

Pharmacodynamics

[edit]
See also: Pharmacology of antidepressants and Tricyclic antidepressant § Binding profiles
Desipramine[15]
Site Ki (nM) Species Ref
SERTTooltip Serotonin transporter 17.6–163 Human [16][17]
NETTooltip Norepinephrine transporter 0.63–3.5 Human [16][17]
DATTooltip Dopamine transporter 3,190 Human [16]
5-HT1A ≥6,400 Human [18][19]
5-HT2A 115–350 Human [18][19]
5-HT2C 244–748 Rat [20][21]
5-HT3 ≥2,500 Rodent [21][22]
5-HT7 >1,000 Rat [23]
α1 23–130 Human [18][24][17]
α2 ≥1,379 Human [18][24][17]
β ≥1,700 Rat [25][26]
Cav2.2 410 Human [27]
D1 5,460 Human [28]
D2 3,400 Human [18][24]
H1 60–110 Human [18][24][29]
H2 1,550 Human [29]
H3 >100,000 Human [29]
H4 9,550 Human [29]
mAChTooltip Muscarinic acetylcholine receptor 66–198 Human [18][24]
  M1 110 Human [30]
  M2 540 Human [30]
  M3 210 Human [30]
  M4 160 Human [30]
  M5 143 Human [30]
σ1 1,990–4,000 Rodent [31][32]
σ2 ≥1,611 Rat [15][32]
Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site.

Desipramine is a very potent and relatively selective norepinephrine reuptake inhibitor (NRI), which is thought to enhance noradrenergic neurotransmission.[33][34] Based on one study, it has the highest affinity for the norepinephrine transporter (NET) of any other TCA,[16] and is said to be the most noradrenergic[35] and the most selective for the NET of the TCAs.[33] The observed effectiveness of desipramine in the treatment of ADHD was the basis for the development of the selective NRI atomoxetine and its use in ADHD.[33]

Desipramine has the weakest antihistamine and anticholinergic effects of the TCAs.[36][35][37] It tends to be slightly activating/stimulating rather than sedating, unlike most others TCAs.[35] Whereas other TCAs are useful for treating insomnia, desipramine can cause insomnia as a side effect due to its activating properties.[35] The drug is also not associated with weight gain, in contrast to many other TCAs.[35] Secondary amine TCAs like desipramine and nortriptyline have a lower risk of orthostatic hypotension than other TCAs,[38][39] although desipramine can still cause moderate orthostatic hypotension.[40]

Pharmacokinetics

[edit]

Desipramine is the major metabolite of imipramine and lofepramine.[41]

Chemistry

[edit]

Desipramine is a tricyclic compound, specifically a dibenzazepine, and possesses three rings fused together with a side chain attached in its chemical structure.[42] Other dibenzazepine TCAs include imipramine (N-methyldesipramine), clomipramine, trimipramine, and lofepramine (N-(4-chlorobenzoylmethyl)desipramine).[42][43] Desipramine is a secondary amine TCA, with its N-methylated parent imipramine being a tertiary amine.[44][45] Other secondary amine TCAs include nortriptyline and protriptyline.[46][47] The chemical name of desipramine is 3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N-methylpropan-1-amine and its free base form has a chemical formula of C18H22N2 with a molecular weight of 266.381 g/mol.[1] The drug is used commercially mostly as the hydrochloride salt; the dibudinate salt is or has been used for intramuscular injection in Argentina (brand name Nebril) and the free base form is not used.[1][2] The CAS Registry Number of the free base is 50-47-5, of the hydrochloride is 58-28-6, and of the dibudinate is 62265-06-9.[1][2][48]

History

[edit]

Desipramine was developed by Geigy.[49] It first appeared in the literature in 1959 and was patented in 1962.[49] The drug was first introduced for the treatment of depression in 1963 or 1964.[49][50]

Society and culture

[edit]

Generic names

[edit]

Desipramine is the generic name of the drug and its INNTooltip International Nonproprietary Name and BANTooltip British Approved Name, while desipramine hydrochloride is its USANTooltip United States Adopted Name, USPTooltip United States Pharmacopeia, BANTooltip British Approved Name, and JANTooltip Japanese Accepted Name.[1][2][51][3] Its generic name in French and its DCFTooltip Dénomination Commune Française are désipramine, in Spanish and Italian and its DCITTooltip Denominazione Comune Italiana are desipramina, in German is desipramin, and in Latin is desipraminum.[2][3]

Brand names

[edit]

Desipramine is or has been marketed throughout the world under a variety of brand names, including Irene, Nebril, Norpramin, Pertofran, Pertofrane, Pertrofran, and Petylyl among others.[2][3]

References

[edit]
[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Desipramine

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from Grokipedia
Desipramine is a (TCA) medication that functions as a secondary and the of , primarily approved for the treatment of . Developed by Geigy in the late 1950s, it first appeared in scientific literature in 1959, was patented in 1962, and received FDA approval in 1964 for marketing as an oral tablet under the brand name Norpramin. Desipramine exerts its therapeutic effects mainly by inhibiting the presynaptic of norepinephrine and, to a lesser extent, serotonin in the , thereby increasing the availability of these neurotransmitters in the synaptic cleft. It also demonstrates secondary pharmacological activities, including antagonism at alpha-1 adrenergic, H1, and muscarinic receptors, which contribute to its side effect profile. The drug is well-absorbed orally, with peak plasma concentrations reached in 4 to 6 hours, a ranging from 7 to over 60 hours, and primary metabolism via hepatic enzymes such as and , followed by urinary excretion. Therapeutic plasma levels typically range from 50 to 300 ng/mL. In addition to its FDA-approved indication for depression in adults, desipramine has off-label applications for conditions including , attention-deficit/hyperactivity disorder (ADHD), , , and , though its use has declined since the 1990s in favor of newer agents like selective serotonin reuptake inhibitors (SSRIs) due to a more favorable side effect profile in the latter. Dosing typically begins at 25 to 75 mg daily for adults, titrated up to a maximum of 300 mg per day based on response and tolerance, with lower doses for adolescents and the elderly. Common adverse effects include anticholinergic symptoms such as dry mouth, , , and , as well as , , and . More serious risks encompass cardiac arrhythmias, seizures, and an increased suicidality in children, adolescents, and young adults under 25, necessitating close monitoring during initiation and dose adjustments. Desipramine is contraindicated in patients taking inhibitors (MAOIs), those with recent , or hypersensitivity to dibenzazepines, and it carries a high overdose potential, with cardiac conduction abnormalities being a leading cause of fatality.

Introduction

Description and Classification

Desipramine is a (TCA) primarily used in the management of . It serves as the active metabolite of , another TCA, formed through hepatic metabolism via enzymes such as CYP2C19. Chemically, desipramine is classified as a dibenzazepine derivative, characterized by its tricyclic structure consisting of two rings fused to a central ring, along with a secondary amine side chain that contributes to its pharmacological profile. Tricyclic antidepressants as a class emerged in the and 1960s, evolving from antihistamine and antipsychotic research; , the prototype TCA, was approved by the FDA in 1959 for depression treatment, paving the way for subsequent agents like desipramine. A key distinguishing feature of desipramine among TCAs is its selective norepinephrine inhibition (NRI), exhibiting approximately 400-fold greater potency in blocking norepinephrine transporters compared to serotonin transporters, resulting in minimal serotonergic effects relative to other TCAs like . In contemporary therapeutic positioning, desipramine is not regarded as a first-line option for depression due to its adverse effect profile, including and cardiovascular risks, but it remains relevant for treatment-resistant cases where selective noradrenergic enhancement may provide benefit.

Therapeutic Role

Desipramine, a (TCA) with selective norepinephrine inhibition, serves as a secondary option in modern psychiatric treatment for , particularly when first-line agents like selective serotonin inhibitors (SSRIs) or serotonin-norepinephrine inhibitors (SNRIs) fail to achieve remission. While SSRIs and SNRIs are favored for their lower risk of cardiac toxicity and overdose, desipramine may offer advantages in melancholic depression, where it has demonstrated efficacy at plasma concentrations around 115 ng/mL, addressing core symptoms such as and psychomotor disturbances more effectively than . Its norepinephrine-centric action also aligns with the needs of patients experiencing atypical or anergic depression, characterized by low energy, , and increased appetite, potentially providing targeted symptomatic relief in these subtypes. In treatment algorithms for depression, desipramine is typically positioned as a third-line intervention following inadequate response to SSRIs or SNRIs, with particular utility in cases or when comorbid attention-deficit/hyperactivity disorder (ADHD) is present, as it leads to response in approximately 68% of adults while treating depressive features. Meta-analyses from the confirm TCAs' efficacy comparable to each other for acute depression treatment, though they show higher dropout rates than SSRIs like due to side effects. Relative to amitriptyline, another TCA, desipramine exhibits improved tolerability with reduced and burden, making it a preferable within its class for patients sensitive to these effects. Despite these roles, desipramine's use is tempered by significant limitations, including a warning from the FDA highlighting an increased risk of and behavior in children, adolescents, and young adults under 25 during initial treatment phases. It is generally avoided in elderly patients owing to heightened risks of falls from and confusional states, with guidelines recommending lower doses or alternatives in this population. guidelines reinforce TCAs like desipramine for but emphasize their role only after optimizing first- and second-line therapies, underscoring ongoing concerns about safety in vulnerable groups.

Medical Applications

Approved Indications

Desipramine, marketed as Norpramin, received FDA approval in 1964 as a for the treatment of (MDD) in adults. Clinical trials from the and established its efficacy, with response rates typically ranging from 50% to 60% in reducing symptoms as measured by the Hamilton Depression Rating Scale (HDRS). For instance, meta-analyses of , including desipramine, have shown that 56% to 60% of patients achieve significant improvement compared to 42% to 47% on . Systematic reviews, such as those evaluating antidepressants for depression, confirm desipramine's comparable efficacy to other antidepressants in adults, though it is now considered a second-line option due to side effect profiles. Although desipramine has been investigated for pediatric applications like and ADHD, current FDA labeling specifies it is not approved for use in children, with and not established in this population. Recent pediatric guidelines from the 2020s emphasize behavioral therapies as first-line for , limiting pharmacological options like to cases under specialist supervision.

Off-Label and Investigational Uses

Desipramine has been explored off-label for the treatment of attention-deficit/hyperactivity disorder (ADHD) in both children and adults, leveraging its noradrenergic effects to improve core symptoms such as inattention and hyperactivity. Small randomized controlled trials (RCTs) in children and adolescents have demonstrated efficacy, with desipramine showing benefits comparable to stimulants in reducing ADHD symptoms as rated by teachers and physicians. However, the use of desipramine for treating ADHD in children became controversial in the early 1990s due to reports of rare sudden cardiac deaths in a small number of children, even at normal therapeutic doses. These incidents, including cases reported in 1990 and subsequent years, prompted the FDA to issue warnings and led to a significant reduction in its pediatric use. In adults, it is used off-label when first-line stimulants are ineffective or contraindicated, though evidence is derived from smaller studies and expert consensus rather than large-scale trials. A 2013 confirmed desipramine's role among antidepressants as effective for ADHD, particularly in pediatric populations, based on controlled trials. Desipramine has also been used off-label for , where controlled studies have shown significant reductions in binge-eating frequency (e.g., 91% decrease compared to in a double-blind trial). Evidence from systematic reviews supports antidepressants like desipramine for reducing bulimic symptoms, though it is considered second-line due to side effects. Another off-label application is in , particularly , where low doses (typically 25-75 mg/day) have shown symptom reduction in 1990s studies. A double-blind RCT comparing desipramine to and in patients found significant improvements in pain scores via observer and self-ratings. However, a 2014 Cochrane review assessed the overall evidence for desipramine in as very low quality under GRADE criteria, citing limited trials, small sample sizes, and high risk of , with uncertain benefits outweighing harms. Investigational uses include , where Phase II-era trials in the 1990s and 2000s evaluated desipramine for promoting and reducing cravings, often with mixed outcomes. A 1991 of six placebo-controlled trials (n=200) indicated desipramine facilitated initial cocaine in outpatient settings, though long-term efficacy was inconsistent due to high dropout rates. A 2005 RCT in -dependent patients with comorbid depression reported mood improvements correlated with reduced cocaine use, supporting its potential in dual-diagnosis cases. Desipramine has also been investigated at low doses for functional dyspepsia and related functional bowel disorders, aiming to alleviate through . A 2005 RCT found low-dose desipramine superior to in reducing postprandial symptoms in functional bowel disease patients, though per-protocol analysis showed borderline significance. Broader evidence from TCA class meta-analyses in the 2010s supports low-dose tricyclics for functional gastrointestinal pain, with desipramine occasionally referenced in guidelines for . Overall, evidence for these off-label and investigational uses is low to moderate quality, with GRADE ratings often very low for applications due to methodological limitations and sparse data. Recent reviews highlight desipramine's potential in ADHD augmentation with stimulants in cases, though dedicated RCTs remain limited. Ongoing focuses on therapies, but no large-scale trials for involving desipramine were identified post-2020.

Administration and Dosage

Dosing Guidelines

Desipramine dosing for typically begins at 25–50 mg orally once daily or in divided doses, with gradual titration by 25–50 mg increments weekly based on clinical response and tolerability, aiming for a of 100–200 mg per day; the maximum recommended dose is 300 mg per day, generally reserved for hospitalized patients under close supervision. In special populations, dosing requires reduction to minimize risks. For elderly patients, initiate at 10–25 mg once daily at , cautiously to a maximum of 100–150 mg per day due to increased sensitivity to and cardiovascular effects. In hepatic impairment, use lower starting doses and slower , as desipramine undergoes extensive hepatic , potentially leading to accumulation. Desipramine is not FDA-approved for patients under 18 years due to suicidality risks; off-label pediatric use requires specialist oversight. poor metabolizers may require dose reductions of 50% or more, with plasma level monitoring to avoid , as they exhibit 2–10-fold higher concentrations compared to normal metabolizers. Monitoring is essential for safe use, per FDA labeling and VA/DoD guidelines updated in 2022. Obtain baseline ECG and monitor periodically for QT prolongation, particularly at doses over 100 mg per day or in patients with cardiac risk factors, as desipramine can cause interval changes. Therapeutic plasma levels, while not definitively established by FDA, are commonly targeted at 50–300 ng/mL to guide dosing and assess compliance or toxicity. Initial weekly clinical assessments for suicidality are required in younger patients, with prescriptions limited to small quantities to mitigate overdose risk; in scenarios, especially with inhibitors like SSRIs, enhanced monitoring for interactions and adverse effects is advised, reflecting 2025 emphases on high-risk combinations in older adults.

Pharmacological Forms

Desipramine is formulated exclusively as oral tablets of the salt, which provides enhanced stability and for pharmaceutical use. Available strengths include 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, and 150 mg tablets, allowing for flexible dosing adjustments based on needs. No intravenous, topical, or other non-oral formulations exist, limiting administration to the oral route. To reduce the risk of gastrointestinal upset, tablets should be taken with , and despite the drug's variable plasma half-life of 7 to over 60 hours, once-daily dosing—often at bedtime—is feasible for maintenance therapy. The brand-name product Norpramin is available only in tablet form, while generic desipramine hydrochloride has been widely accessible since the expiration in the late . As of 2025, generic desipramine tablets have been discontinued by several manufacturers, resulting in limited availability; the brand Norpramin remains accessible in some markets.

Safety Profile

Adverse Effects

Desipramine, a (TCA), is associated with various adverse effects attributable to its and noradrenergic mechanisms. Common effects include dry mouth and . Noradrenergic effects often present as and , which can contribute to and falls. These effects are generally dose-dependent and more prominent during initial treatment phases. Serious adverse effects, though less frequent, warrant careful monitoring. Cardiac arrhythmias, such as and QT prolongation, pose significant risks, particularly in patients with preexisting cardiovascular conditions. In the early 1990s, reports linked desipramine to rare sudden cardiac deaths in a small number of children treated for behavioral disorders like ADHD, even at normal doses, leading to FDA warnings and reduced use in pediatrics. Seizures represent a key concern due to a lowered . is possible but typically less substantial compared to other TCAs like amitriptyline or . An increased risk of suicidality has been observed in children, adolescents, and young adults, necessitating close monitoring. Post-marketing from the FDA highlight these risks, with overall adverse reaction rates derived from voluntary reports and clinical trials. Risk factors for adverse effects include advanced age, where elderly patients exhibit higher overall incidence (up to 39% for major reactions versus 7% in younger adults), partly due to increased susceptibility to and falls from impaired renal clearance and altered . Concomitant use of antipsychotics can elevate rates to 32%. Guidelines recommend ECG monitoring in TCA users to detect QT prolongation and arrhythmias early. Management of adverse effects primarily involves dose reduction or discontinuation, with symptomatic relief for milder symptoms like dry mouth through hydration or sialogogues. Desipramine's relatively lower sedating profile compared to amitriptyline may reduce somnolence-related issues, though individual variability persists. Certain drug interactions can amplify these effects, such as those with QT-prolonging agents.

Drug Interactions and Contraindications

Desipramine, a , undergoes significant interactions with cytochrome P450 2D6 () inhibitors, such as fluoxetine, paroxetine, and quinidine, which can elevate desipramine plasma concentrations by 2- to 10-fold, particularly in poor metabolizers, increasing the risk of toxicity including cardiac arrhythmias and seizures. Concomitant use with monoamine oxidase inhibitors (MAOIs), including and , is contraindicated due to the potential for life-threatening ; a washout period of at least 14 days is required before initiating desipramine after MAOI discontinuation, and vice versa. Drugs that prolong the , such as certain antipsychotics (e.g., ) and antiarrhythmics (e.g., quinidine), can amplify desipramine's cardiotoxic effects, leading to enhanced risk of ; electrocardiographic monitoring is recommended in such cases. Alcohol consumption exacerbates desipramine's depressant effects, intensifying sedation and impairing psychomotor performance, which heightens the danger in overdose scenarios. Case reports have documented fatalities associated with these interactions, including from MAOI combinations and severe toxicity from inhibition leading to elevated levels and multi-organ failure. Absolute contraindications to desipramine include the acute recovery phase following , to desipramine or other dibenzazepines, and concurrent or recent (within 14 days) MAOI use. Relative contraindications encompass narrow-angle , due to anticholinergic-induced intraocular pressure elevation, and , where desipramine may precipitate manic episodes. In , desipramine is not assigned a formal FDA category but should be used only if the potential benefit justifies the risk, as human data are limited and inconclusive; symptoms have been reported in exposed infants. For elderly patients, the 2023 American Geriatrics Society strongly recommend avoiding desipramine due to its strong properties, which increase risks of falls, , and , especially in contexts.

Overdose and Toxicity

Clinical Presentation

Desipramine overdose manifests through a triad of , cardiovascular, and (CNS) effects, often progressing rapidly within hours of ingestion. symptoms include , , , , dry mouth, and , resulting from muscarinic receptor blockade. Cardiovascular manifestations are prominent and life-threatening, featuring , , arrhythmias such as or fibrillation, and conduction abnormalities like prolonged PR and QT intervals. CNS effects range from agitation and to severe seizures, , and respiratory depression, contributing to high morbidity. The centers on desipramine's potent blockade of voltage-gated sodium channels in myocardial and neuronal tissues, leading to slowed conduction and membrane stabilization failure. This manifests electrocardiographically as widening (>100 ms predictive of seizures, >160 ms of ventricular arrhythmias), in lead aVR, and a sine-wave pattern in severe cases. Case series from the 1970s through the 2020s, including pediatric and adult overdoses, consistently document these ECG changes as harbingers of , with desipramine exhibiting higher than other antidepressants due to its noradrenergic selectivity. Recent 2024 updates reaffirm that QRS prolongation remains a key prognostic indicator, though its incidence has declined with reduced prescribing of tricyclics. A dose exceeding 10 mg/kg is often associated with severe toxicity and fatality in desipramine overdose, with the lowest reported around 15 mg/kg across antidepressants; desipramine specifically shows severe effects at doses as low as 6 mg/kg in children. Mortality rates from overdoses, including desipramine, are approximately 1-2% among cases reaching medical facilities with prompt treatment, though desipramine carries a disproportionately higher (up to 2-3 times that of amitriptyline or based on poison control data). Risk factors for desipramine overdose include intentional self-poisoning in patients with depression, given its primary use as an , and accidental ingestions in , where even small amounts (e.g., 5-10 mg/kg) can prove fatal due to the drug's narrow . Therapeutic doses may occasionally mimic mild overdose symptoms like dry mouth or , but these are far less severe than in supratherapeutic exposures.

Management Strategies

Management of desipramine overdose, a tricyclic antidepressant (TCA), follows evidence-based protocols emphasizing rapid stabilization, decontamination, and targeted interventions to address cardiotoxicity, the primary cause of morbidity and mortality. Initial response prioritizes the ABCs—airway management with possible intubation for coma or respiratory depression, breathing support via oxygenation or ventilation, and circulation assessment with intravenous access for fluid resuscitation. Decontamination involves administration of activated charcoal (1 g/kg orally) if ingestion occurred within 2 hours and the airway is protected, as it binds TCAs in the gastrointestinal tract and reduces absorption, though its efficacy diminishes beyond this window. For , the cornerstone intervention is , indicated when QRS duration exceeds 100 ms on ECG, persists, or ventricular arrhythmias occur. Dosing typically starts with a bolus of 1–2 mEq/kg, followed by an infusion (e.g., 150 mEq in 1 L of D5W at 1.5–2 times maintenance rate) to achieve serum 7.45–7.55, which enhances sodium channel unbinding and stabilizes membranes. In cases, intravenous lipid emulsion (20% solution, 1.5 mL/kg bolus then 0.25 mL/kg/min infusion) may be used for persistent hemodynamic instability, based on case reports showing improved cardiac function in lipophilic TCA overdoses like desipramine. For life-threatening shock or arrest, venoarterial (VA-ECMO) provides circulatory support, as recommended in 2023 guidelines for toxicities. Ongoing monitoring includes continuous ECG to track QRS widening and (QRS >160 ms predicts high arrhythmia risk), serial serum TCA levels (though not directly correlative with toxicity severity), and . Seizures, common in TCA overdose, are managed supportively with benzodiazepines (e.g., 0.05–0.1 mg/kg IV) as first-line therapy, escalating to or if refractory. Hypertonic saline serves as an alternative to for alkalization in patients with contraindications like , targeting similar goals while providing sodium loading. Evidence from the American Association of Poison Control Centers (AAPCC) National Poison Data System indicates improved outcomes with early intervention; for instance, in 2004 data, among over 9,300 treated TCA exposures, only 85 fatalities occurred, yielding survival rates exceeding 99% for managed cases, though many were mild. Recent poison control updates, including 2023 AAPCC reports and texts, reinforce these protocols, noting decreased mortality (now <5–10%) due to timely bicarbonate and supportive care, with desipramine-specific thresholds for referral at ingestions >2.5 mg/kg. Long-term care involves psychiatric evaluation for intentional overdose and monitoring for delayed complications like .

Pharmacology

Pharmacodynamics

Desipramine primarily acts as a potent inhibitor of the (), preventing the of norepinephrine into presynaptic neurons with a high affinity (Ki = 0.83 nM at cloned receptors). It exhibits weaker inhibition of the (), with a Ki of 25 nM, resulting in a selectivity ratio favoring NET by approximately 30-fold. Desipramine also displays secondary pharmacological effects, including blockade of alpha-1 adrenergic receptors (Ki = 100 nM) and mild antagonism at H1 receptors (Ki ≈ 110 nM). It lacks significant affinity for the (), with Ki values exceeding 10,000 nM, thereby exerting minimal direct influence on dopaminergic . By blocking , desipramine elevates extracellular norepinephrine levels in key brain regions such as the and , enhancing stimulation of postsynaptic beta-adrenergic receptors. This increased noradrenergic signaling contributes to therapeutic effects like mood stabilization and alleviation of depressive symptoms through downstream activation of cyclic AMP pathways and changes in neuronal plasticity. With chronic administration, desipramine induces downregulation of beta-adrenergic receptors, which may underlie adaptive responses and long-term efficacy in treating mood disorders. Compared to its parent compound , which shows balanced but less selective inhibition (Ki = 20 nM for and 1.3 nM for SERT), desipramine demonstrates greater noradrenergic specificity. The extent of transporter inhibition can be quantified using the fractional occupancy model: Fractional occupancy=[D]Ki+[D]\text{Fractional occupancy} = \frac{[D]}{K_i + [D]} where [D][D] represents the free drug concentration and KiK_i is the inhibition constant; at therapeutic plasma levels (typically 100–300 ng/mL, approximately 375–1125 nM), desipramine achieves near-complete occupancy while only partially occupying SERT. Recent studies, including (PET) assessments of binding in patients with , have confirmed that inhibitors like desipramine reduce transporter availability in noradrenergic pathways, correlating with symptomatic improvement after prolonged treatment.

Pharmacokinetics

Desipramine exhibits moderate oral of approximately 40-70%, reflecting variability due to extensive first-pass hepatic following gastrointestinal absorption. Peak plasma concentrations (T_max) are typically reached 4-6 hours after oral dosing. The is widely distributed throughout the body, with a (V_d) ranging from 10-50 L/kg, attributed to its high and tissue binding. Protein binding to plasma proteins is 73-92%, and desipramine readily crosses the blood-brain barrier, facilitating its effects. Metabolism occurs primarily in the liver via the enzyme , forming the active metabolite 2-hydroxydesipramine through 2-hydroxylation. Minor pathways involve CYP1A2-mediated 10-hydroxylation and N-demethylation. The elimination half-life of desipramine averages 12-30 hours but can extend significantly (up to 60 hours or more) in individuals with reduced activity. Excretion is predominantly renal, with approximately 70% of the dose recovered in , primarily as metabolites; less than 5% is eliminated unchanged. Total clearance varies widely, typically 40-110 L/h, influenced by metabolic capacity. Pharmacokinetic variability is largely driven by genetic polymorphisms in , with 5-10% of Caucasians classified as poor metabolizers (PMs) exhibiting reduced clearance and prolonged , leading to higher plasma concentrations. Intermediate metabolizers (IMs) show moderate reductions in clearance, while ultrarapid metabolizers (UMs) may require higher doses for . According to CPIC guidelines for antidepressants, dosing adjustments are recommended: standard dosing for normal metabolizers, 25% dose reduction for IMs, 50% reduction for PMs with , and consideration of alternatives or higher doses with monitoring for UMs. Steady-state plasma concentrations (C_ss) can be estimated using the formula: Css=DoseCL×τC_{ss} = \frac{\text{Dose}}{CL \times \tau} where CL is clearance and \tau is the dosing interval; this is particularly useful in pharmacogenomically guided dosing to avoid toxicity in PMs.

Chemistry

Chemical Structure and Properties

Desipramine, chemically known as 3-(10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)-N-methylpropan-1-amine, is a tricyclic dibenzazepine derivative with the molecular formula C18H22N2 and a molecular weight of 266.38 g/mol. Its IUPAC name is 3-(5,6-dihydrobenzobenzazepin-11-yl)-N-methylpropan-1-amine, and the SMILES notation is CNCCCN1C2=CC=CC=C2CCC3=CC=CC=C31. The core structure consists of a seven-membered azepine ring fused to two benzene rings, with a propylamine side chain at the nitrogen position bearing a methyl group. In its hydrochloride salt form, desipramine appears as a to off-white crystalline . It exhibits basic properties with a pKa of approximately 10.15 for the aliphatic group. The has limited in (about 58.6 mg/L at 24°C), but the salt is more soluble, dissolving at a rate of 1 g in 20 mL of , and is also freely soluble in alcohol and while being insoluble in . Desipramine hydrochloride is sensitive to prolonged exposure to light, heat, and air, which can lead to degradation. It should be stored at in a tightly closed container to maintain stability. As the primary active demethylated metabolite of , desipramine retains the characteristic ring system of its parent compound while exhibiting enhanced selectivity for norepinephrine inhibition.

Synthesis and Metabolism

Desipramine is synthesized through a multi-step process starting from iminodibenzyl (10,11-dihydro-5H-dibenz[b,f]), involving with 1-bromo-3-chloropropane in the presence of to form 5-(3-chloropropyl)-10,11-dihydro-5H-dibenz[b,f], followed by reaction with to yield desipramine. This route, which includes key steps of and substitution, was patented in 1962 by Geigy as British Patent 908,788 for the and forms. Alternative synthetic approaches include direct N-demethylation of or reduction of N-oxide, though isotope-trapping studies indicate that N-oxide is not an obligatory intermediate in desmethylation pathways. Overall yields for normethyl precursor synthesis from iminodibenzyl typically reach 35%. Purity of desipramine is routinely assessed using reversed-phase (RP-HPLC) methods, which enable quantification with , often achieving detection limits suitable for pharmaceutical-grade analysis exceeding 98% purity. In vivo, desipramine is primarily metabolized in the liver via aromatic to the 2-hydroxydesipramine, mediated mainly by the enzyme , with minor contributions from CYP1A2. This pathway exhibits genetic variability influenced by polymorphisms, leading to differences in metabolite formation and drug clearance. Further transformations include of hydroxy metabolites for excretion, though N-demethylation to primary amines occurs to a lesser extent compared to . No significant environmental concerns have been noted in standard synthesis processes for desipramine.

History and Development

Discovery and Early Research

Desipramine, also known as desmethylimipramine or G-35020, was first identified in 1959 by chemists at the pharmaceutical company J.R. Geigy in , , as the principal of , the first . This discovery stemmed from metabolic studies on , revealing desipramine's independent pharmacological potential, leading to its separate synthesis with a Swiss priority date of September 4, 1959. Early isolation efforts focused on its structural similarity to but with a secondary configuration, prompting targeted evaluation for activity beyond its role as a . Preclinical research in the late and early , building on 's established effects, utilized animal models to explore desipramine's mechanism, particularly its influence on norepinephrine. Studies in rats demonstrated that desipramine rapidly reversed reserpine-induced and ptosis—behavioral indicators of monoamine depletion—more potently than , suggesting enhanced noradrenergic activity through selective inhibition of norepinephrine at peripheral sympathetic nerves. Key experiments by Carlsson et al. (1961), Dengler et al. (1961), and Axelrod et al. (1961) confirmed this selectivity , showing desipramine's preferential blockade of norepinephrine uptake over serotonin, unlike the broader profile of . However, overdose models in raised early concerns about , with high doses inducing arrhythmias and convulsions similar to , attributed to blockade and heightened noradrenergic stimulation. The first human trials commenced in 1962, with preliminary investigations evaluating desipramine's safety and efficacy in small cohorts of depressed patients, often comparing it directly to in Phase I studies. These open-label assessments, such as those by Azima et al. and Ban and Lehmann, reported rapid onset of antidepressant effects at doses of 75–150 mg daily, with improvements in and noted within one week, supporting its noradrenergic selectivity observed in animals. A landmark 1963 publication in Psychopharmacologia detailed a controlled comparison in normal subjects and depressive patients, confirming desipramine's efficacy comparable to but with fewer side effects and a profile favoring noradrenergic symptoms. By 1964, cumulative 1960s trial data from over 100 patients underscored this selectivity, with desipramine showing superior response in vital depressions characterized by low energy, though initial reports highlighted risks of and in sensitive individuals.

Regulatory Milestones

Desipramine was first approved by the U.S. (FDA) on December 18, 1964, under the brand name Pertofrane for the treatment of depression. This approval marked it as one of the early antidepressants available in the United States, following closely after in 1959. Generic versions of desipramine entered the U.S. market in the late 1980s, with the FDA granting approval to Totowa on June 5, 1987, for oral tablets in various strengths. Additional generic approvals followed, reflecting the expiration of original patents and increased competition, which improved accessibility for patients. In the early 1990s, reports of rare sudden cardiac deaths in a small number of children treated with desipramine at therapeutic doses, primarily for attention deficit hyperactivity disorder (ADHD), prompted FDA responses including label updates advising caution for pediatric use. These reports, first documented in 1990 with three cases and followed by additional incidents, led to heightened scrutiny and a significant reduction in its prescription for children. Internationally, desipramine received marketing authorization in shortly after its U.S. debut, with initial approvals in the mid-1960s, including by regulatory bodies equivalent to the modern (EMA). However, in some countries such as the , its use has diminished since the due to the availability of safer alternatives with fewer cardiac risks. Post-marketing surveillance led to significant label updates. In 2004, the FDA issued a warning for all antidepressants, including desipramine, highlighting an increased risk of suicidality in pediatric patients. This warning was expanded in May 2007 to include young adults aged 18 to 24 years, based on analyses showing elevated risks during initial treatment phases. In the , product labels were revised to emphasize cardiac monitoring, recommending ECG assessments and vital sign checks due to potential effects on and conduction, particularly in patients with preexisting cardiovascular conditions. As of 2025, the FDA continues to restrict pediatric use of desipramine, with labels explicitly stating it is not approved for patients under 18 due to insufficient evidence of efficacy and heightened suicidality risks, reinforcing longstanding post-approval precautions.

Society and Culture

Generic and Brand Names

Desipramine is the international nonproprietary name (INN) assigned by the World Health Organization for this tricyclic antidepressant. The United States Adopted Name (USAN) is desipramine hydrochloride, referring to the commonly used salt form of the drug. In the United States, desipramine is primarily available under the brand name Norpramin, marketed by Validus Pharmaceuticals LLC since its FDA approval. Internationally, it has been sold under various brand names, including Pertofrane (originally by Ciba-Geigy and later USV), which was widely used in but has been discontinued in several markets. Desipramine was first introduced commercially by Geigy Pharmaceuticals in under early branding associated with Pertofrane. Linguistic variations of the generic name appear in non-English markets, such as desipramina in Spanish-speaking regions like and . In French-speaking countries, it is denoted as désipramine. In recent years, generic versions of desipramine hydrochloride have become available in emerging markets, including , where it is distributed through pharmaceutical exporters without prominent proprietary branding. In the United States, desipramine is classified as a prescription-only medication (Rx-only) and is not a controlled substance under the DEA schedules, making it widely available in generic form from multiple manufacturers. Internationally, desipramine remains available by prescription in Canada, where it is approved and marketed by companies such as Apotex Inc. and AA Pharma Inc., though tricyclic antidepressants (TCAs) like desipramine face restrictions in some contexts due to safety concerns including cardiac risks and overdose potential. In the European Union, desipramine is authorized for specific uses but with limitations on TCA prescriptions, often requiring specialist oversight and black-box warnings for suicidality and cardiovascular effects; its orphan drug designation for conditions like Rett syndrome was withdrawn in 2017. In contrast, desipramine was withdrawn from the Australian market in the early 2000s following manufacturer discontinuation due to low profitability and shifts toward newer antidepressants, rendering it unavailable despite efforts by psychiatric organizations to retain it. Desipramine has experienced periodic supply shortages in the , including ongoing issues reported from 2022 through 2024 and into 2025, primarily affecting generic tablet formulations due to manufacturing delays and market discontinuations by some suppliers; as of 2025, Avet Pharmaceuticals discontinued all strengths, followed by a recall of nine lots in October 2025, though generics remain available from other manufacturers such as and Teva. The generic form of desipramine is inexpensive, typically costing $10–20 per month for a standard 30-tablet supply at common dosages, and it is not available over-the-counter anywhere. Desipramine is not included on the 2025 WHO Model List of , though alternative TCAs such as amitriptyline and are listed for depressive disorders.

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