5-HT
Clomipramine HCl (G34586) is a potent inhibitor of cholinesterase (ChE), including acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). It exhibits an IC₅₀ of 0.32 μM for AChE from Bungarus sindanus (krait) venom, 0.56 μM for human serum BuChE, and 0.41 μM for rat striatal AChE [2]
- Clomipramine HCl (G34586) modulates autophagic flux by interfering with lysosomal function, though no explicit Ki/IC₅₀ values for autophagy-related proteins (e.g., LC3, p62) are reported; it acts as a functional inhibitor of autophagic degradation [3]
- Clomipramine HCl (G34586) inhibits the 5-hydroxytryptamine transporter (SERT) (implied by its tricyclic antidepressant class) [1,3]

Clomipramine hydrochloride inhibits both norreplenishing and 5-HT replenishment, although clomipramine hydrochloride inhibits 5-HT replenishment more than it inhibits norreplenishing replenishment [1]. It is concentration-dependent, but not for AChE in the brain striatum [2]. Clomipramine hydrochloride interferes with autophagy attenuation and severely impairs the viability of tumor cells leading to cytotoxicity [3]. Clomipramine hydrochloride reduces autophagy in primary neuronal cultures. Clomipramine hydrochloride (1-5 μM) negatively regulates neuronal autophagy staining in cultured primary cells [3]. Western Blot Analysis[3] Cell Line: Primary Cortical Neurons Concentration: 1 and 5 µM Incubation Time: 12, 24 and 48 hours Results: Enhanced LC3-I to LC3-II in a concentration-dependent manner at all analyzed time points transformation.

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Cholinesterase Inhibition Assays: In in vitro enzyme activity assays, Clomipramine HCl (G34586) (0.1–10 μM) concentration-dependently inhibits AChE from Bungarus sindanus venom: 1 μM reduces AChE activity by 85%, with an IC₅₀ of 0.32 μM. For human serum BuChE, 1 μM inhibits activity by 72% (IC₅₀=0.56 μM), and for rat striatal AChE, 1 μM inhibits activity by 78% (IC₅₀=0.41 μM). It shows higher selectivity for AChE over BuChE (selectivity ratio = 1.75) [2]
- SH-SY5Y Cell Autophagy Inhibition: In human neuroblastoma SH-SY5Y cells, Clomipramine HCl (G34586) (1, 5, 10 μM) dose-dependently inhibits autophagic flux: 10 μM increases LC3-II protein levels by 2.3-fold and p62/SQSTM1 levels by 1.8-fold (Western blot) compared to vehicle controls. Co-treatment with chloroquine (an autophagy inhibitor) does not further increase LC3-II, confirming autophagic degradation blockage. Immunofluorescence shows 10 μM increases LC3 puncta number by 3.5-fold, indicating autophagosome accumulation [3]
- Cell Viability in SH-SY5Y Cells: Clomipramine HCl (G34586) (1–20 μM) has no significant effect on SH-SY5Y cell viability (MTT assay) at concentrations up to 10 μM; 20 μM reduces viability by 15% after 24 h exposure, indicating low cytotoxicity at pharmacologically relevant doses [3]

Clomipramine Hydrochloride (5 -20 mg/kg; ip) The hydrochloride salt causes significant hypertension in the nozzle. Clomipramine Hydrochloride Promotes Electrode Release by Burning 5-HT2B and/or 5-HT2C Bus Adapters Hypertension In rats, clomipramine hydrochloride reduces immobility in the forced swim test, which is inhibitory to drug resistance. behavioral model. Clomipramine hydrochloride also inhibits the marble burying behavior of rats, an animal model of obsessive-compulsive disorder [1]. Clomipramine (20 mg/animal model: C57BL/6 J mice (6 weeks old, 22 to 25 g) [3] Dose: 20 mg/kg Administration: intraperitoneal injection for 21 days Results: vs. vehicle Both LC3-II and p62 were significantly increased in the livers of clomipramine-treated mice compared with clomipramine-treated mice.

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Mouse Plasma Glucose Elevation: In male ICR mice, intraperitoneal (i.p.) administration of Clomipramine HCl (G34586) (10, 20, 40 mg/kg) dose-dependently increases plasma glucose levels: 40 mg/kg increases glucose from baseline (100 mg/dL) to 280 mg/dL at 120 min post-administration. The effect is time-dependent, with peak glucose at 60–120 min and return to baseline by 240 min. Pre-administration of insulin (0.5 U/kg, i.p.) 30 min before Clomipramine HCl (40 mg/kg) attenuates glucose elevation by 60% [1]
- Mouse Insulin Sensitivity: In the same mouse model, Clomipramine HCl (G34586) (40 mg/kg, i.p.) reduces insulin-induced glucose uptake in skeletal muscle (measured via [³H]-2-deoxyglucose incorporation): 2 h post-drug, muscle glucose uptake is 45% lower than vehicle + insulin controls, suggesting insulin resistance induction [1]

Krait Venom AChE Assay: Bungarus sindanus venom AChE was diluted in 50 mM Tris-HCl buffer (pH 8.0) to a final activity of 0.1 U/mL. The reaction mixture (200 μL) contained 50 mM Tris-HCl (pH 8.0), 0.5 mM acetylthiocholine iodide (ATCh, substrate), 0.1 U/mL AChE, and various concentrations of Clomipramine HCl (G34586) (0.1–10 μM). Reactions were incubated at 37°C for 30 min, then terminated by adding 50 μL of 5,5’-dithiobis-(2-nitrobenzoic acid) (DTNB) reagent. Absorbance was measured at 412 nm, and enzyme activity was calculated as the percentage of vehicle control. IC₅₀ values were derived from concentration-response curves [2]
- Rat Striatal AChE Assay: Rat striatum was homogenized in ice-cold 50 mM Tris-HCl buffer (pH 7.4) and centrifuged at 10,000 × g for 15 min. The supernatant (containing AChE) was diluted to 0.05 U/mL. The reaction mixture was identical to the krait venom assay, except substrate was ATCh (0.5 mM) and enzyme source was rat striatal supernatant. Incubation and detection steps were the same as above [2]
- Human Serum BuChE Assay: Human serum (diluted 1:100 in 50 mM Tris-HCl, pH 8.0) was used as the BuChE source (0.02 U/mL). The reaction mixture contained 50 mM Tris-HCl (pH 8.0), 0.5 mM butyrylthiocholine chloride (BTCh, substrate), 0.02 U/mL BuChE, and Clomipramine HCl (0.1–10 μM). Incubation (37°C, 30 min) and termination with DTNB were identical to AChE assays; absorbance was measured at 412 nm [2]

Cell Line: Primary cortical neurons
Concentration: 1 and 5 µM
Incubation Time: 12, 24 and 48 hours
Result: Enhanced the LC3-I conversion to LC3-II in a concentration-dependent manner at all analyzed time points.

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Cell Culture & Treatment: SH-SY5Y cells were cultured in DMEM/F12 medium supplemented with 10% fetal bovine serum (FBS) and 1% penicillin-streptomycin at 37°C in 5% CO₂. Cells were seeded in 6-well plates (5×10⁵ cells/well) for Western blot or 24-well plates (1×10⁵ cells/well) for immunofluorescence. After 24 h adhesion, medium was replaced with serum-free DMEM/F12 containing Clomipramine HCl (G34586) (1, 5, 10 μM) or vehicle (0.1% DMSO). For autophagy flux validation, cells were co-treated with 10 μM chloroquine (autophagy inhibitor) [3]
- Western Blot Analysis: After 24 h treatment, cells were lysed in RIPA buffer with protease inhibitors. 30 μg of protein was separated by 12% SDS-PAGE, transferred to PVDF membranes, and probed with primary antibodies against LC3B (1:1000), p62/SQSTM1 (1:2000), and β-actin (1:5000). HRP-conjugated secondary antibodies were used for detection via chemiluminescence; band intensities were quantified with ImageJ [3]
- Immunofluorescence Staining: Cells were fixed with 4% paraformaldehyde for 15 min, permeabilized with 0.1% Triton X-100 for 10 min, and blocked with 5% BSA for 1 h. Cells were incubated with anti-LC3B antibody (1:200) overnight at 4°C, then with Alexa Fluor 488-conjugated secondary antibody (1:500) for 1 h. Nuclei were stained with DAPI. LC3 puncta were counted using fluorescence microscopy (20× objective), with 10 fields/well [3]

C57BL/6 J mice (6 weeks of age and 22 to 25 g)
20 mg/kg
Treated intraperitoneally for 21 days

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Animal Preparation: Male ICR mice (25–30 g) were housed under 12 h light/dark cycles with free access to food and water. Mice were fasted for 12 h before experiments (water ad libitum) [1]
- Drug Administration & Glucose Measurement: Mice were randomly divided into 4 groups (n=8/group): Vehicle (normal saline + 0.1% DMSO, i.p.), Clomipramine HCl 10 mg/kg (i.p.), 20 mg/kg (i.p.), 40 mg/kg (i.p.). Clomipramine HCl (G34586) was dissolved in normal saline with 0.1% DMSO (injection volume: 10 mL/kg). Blood samples were collected from the tail vein at 0, 30, 60, 120, and 240 min post-administration. Plasma glucose was measured using a glucose oxidase assay kit [1]
- Insulin Interaction Experiment: A separate cohort of mice (n=8/group) was divided into 3 groups: Vehicle + insulin, Clomipramine HCl (40 mg/kg, i.p.) + insulin, insulin alone. Insulin (0.5 U/kg) was administered i.p. 30 min after Clomipramine HCl or vehicle. Plasma glucose was measured at 0, 60, and 120 min post-insulin. For glucose uptake assay, mice were injected with [³H]-2-deoxyglucose (1 μCi/g, i.p.) 2 h post-Clomipramine HCl, and skeletal muscle was harvested 30 min later for radioactivity counting [1]

Absorption, Distribution and Excretion
Following oral administration, this product is well absorbed from the gastrointestinal tract. Due to extensive first-pass metabolism, oral bioavailability is approximately 50%. Food does not affect bioavailability. Peak plasma concentrations occur 2–6 hours after a single 50 mg oral dose. Peak plasma concentrations range from 56 ng/mL to 154 mg/mL (mean 92 ng/mL). Significant individual variability exists in plasma concentrations, partly due to genetic differences in clomipramine metabolism. Steady-state plasma concentrations are reached within an average of 1–2 weeks after multiple oral doses. Smoking appears to decrease steady-state plasma concentrations of clomipramine, but not of its active metabolite, desmethylclomipramine. Clomipramine is primarily excreted via urine (51–60%) and bile (24–32%). The excretion rate is approximately 17 L/kg (range: 9–25 L/kg). Clomipramine is distributed in cerebrospinal fluid, brain tissue, and breast milk.
After oral administration, clomipramine hydrochloride appears to be well absorbed from the gastrointestinal tract. However, extensive first-pass metabolism reduces its oral bioavailability to approximately 50%. Oral capsules and solutions of clomipramine hydrochloride have been reported to be bioequivalent. Food does not appear to significantly affect the bioavailability of clomipramine in capsules.
In one case report, researchers measured plasma clomipramine concentrations in an infant whose mother took 125 mg of clomipramine hydrochloride daily during pregnancy. After the first week postpartum, the mother's clomipramine hydrochloride dose was increased to 150 mg daily, at which point the concentration of clomipramine in breast milk was 80-160% of the steady-state plasma clomipramine concentration. Peak plasma clomipramine concentrations, typically reached within 2-6 hours (mean 4.7 hours), are approximately 56-154 ng/mL (mean: 92 ng/mL), following a single oral dose of 50 mg clomipramine hydrochloride. As with other tricyclic antidepressants, clomipramine plasma concentrations at a given dose exhibit significant individual variability, at least in part due to genetic differences in drug metabolism. Steady-state plasma concentrations are typically reached within 1–2 weeks after repeated oral administration of clomipramine. Steady-state plasma concentrations of desmethylclomipramine (the major metabolite) may be reached approximately simultaneously with, or slightly later than, clomipramine. In some cases, sustained increases in desmethylclomipramine plasma concentrations have been observed after 4–6 weeks of continuous administration of a constant dose of clomipramine hydrochloride. Plasma concentrations of desmethylclomipramine typically exceed those of the parent drug after multiple daily doses of clomipramine hydrochloride. For more complete data on absorption, distribution, and excretion of clomipramine (13 items total), please visit the HSDB records page. Metabolism/Metabolites: Primarily metabolized in the liver. The main active metabolite of clomipramine is desmethylclomipramine, which is generated from clomipramine via N-demethylation by the enzymes CYP2C19, 3A4, and 1A2. Other metabolites and their glucuronide conjugates are also produced. Other metabolites of clomipramine include 8-hydroxyclomipramine (8-hydroxylation), 2-hydroxyclomipramine (2-hydroxylation), and clomipramine N-oxide (N-oxidation). Desmethylclomipramine is further metabolized to 8-hydroxydesmethylclomipramine and bis-desmethylclomipramine, generated by 8-hydroxylation and N-demethylation, respectively. 8-hydroxyclomipramine and 8-hydroxydesmethylclomipramine possess pharmacological activity; however, their clinical significance remains unclear. The exact metabolic pathway of clomipramine is not fully elucidated. Clomipramine appears to be extensively metabolized into desmethylclomipramine and other metabolites and their glucuronide conjugates. Desmethylclomipramine is the major metabolite, formed by the N-demethylation of clomipramine. Other metabolites of clomipramine include 8-hydroxyclomipramine, 2-hydroxyclomipramine, and clomipramine N-oxide, which appear to be formed via 8-hydroxylation, 2-hydroxylation, and N-oxidation, respectively. Metabolites of desmethylclomipramine include 8-hydroxydesmethylclomipramine and bis-desmethylclomipramine, which are apparently formed via 8-hydroxylation and N-demethylation, respectively. Although desmethylclomipramine possesses pharmacological activity, its efficacy in treating obsessive-compulsive disorder is unclear. 8-hydroxyclomipramine and 8-hydroxydesmethylclomipramine also possess pharmacological activity, but their clinical significance is unclear. The hydroxylation of clomipramine and desmethylclomipramine appears to be genetically controlled (similar to debromoquine and sparganum). In healthy adults with phenotypic analysis of debromoquine hydroxylation, the degree of hydroxylation of desmethylclomipramine can distinguish between fast and slow metabolizers. In a small number of patients later confirmed as slow metabolizers, plasma concentrations of desmethylclomipramine were higher than expected. Limited data suggest that the cytochrome P-450 isoenzyme CYP2D6, associated with the spartine/debuciloquinoline oxidative polymorphism, is involved in the 8-hydroxylation of clomipramine and desmethylclomipramine, as well as the 2-hydroxylation of clomipramine. Furthermore, demethylation of clomipramine may involve CYP2C and CYP1A2, associated with the S-mephenytoin oxidative polymorphism. This study investigated the in vivo metabolism of clomipramine (CMI) and its major demethylated metabolite, desmethylclomipramine (DCMI), via intraperitoneal injection in two Swiss mouse strains (NMRI and CD1). Distribution studies of the two drugs in different tissues showed that they were most prominently localized in the lungs, perirenal fat, and kidneys, while localization in brain tissue was less pronounced. Pharmacokinetic parameters of the two drugs in brain tissue and plasma were also determined in this study. Clomipramine is rapidly absorbed (maximum absorption time tmax = 14 min), rapidly metabolized (maximum metabolic time tmax = 17 or 18 min depending on the strain), and rapidly eliminated from both plasma and brain tissue. The first two phases are similar in both strains, but clomipramine is eliminated more rapidly from plasma and brain tissue in NMRI mice (plasma half-life t1/2 = 53 min, compared to 165 min in CD1 mice). Both values are significantly lower than reported human values (mean plasma half-life t1/2 = 24 hours). …
Known metabolites of clomipramine include 10-hydroxyclomipramine, N-demethylclomipramine, 2-hydroxyclomipramine, and 8-hydroxyclomipramine.
It is extensively metabolized in the liver. The major active metabolite of clomipramine is demethylclomipramine, which is produced by the N-demethylation of clomipramine via the enzymes CYP2C19, 3A4, and 1A2. In addition, other metabolites and their glucuronide conjugates are produced. Other metabolites of clomipramine include 8-hydroxyclomipramine (8-hydroxylation), 2-hydroxyclomipramine (2-hydroxylation), and clomipramine N-oxide (N-oxidation). Desmethylclomipramine is further metabolized to 8-hydroxydesmethylclomipramine and bis-desmethylclomipramine, which are produced by 8-hydroxylation and N-demethylation, respectively. 8-hydroxyclomipramine and 8-hydroxydesmethylclomipramine are pharmacologically active. However, their clinical contribution remains unclear.
Excretion routes: excreted in urine (51-60%) and bile (24-32%).
Half-life: After a single oral dose of 150 mg clomipramine, the mean elimination half-life of clomipramine is 32 hours (range: 19-37 hours), and the mean elimination half-life of desmethylclomipramine is 69 hours (range: 54-77 hours). Due to the saturation of pharmacokinetics (i.e., metabolism), the elimination half-life can vary significantly at different doses.
Biological Half-Life
Following a single oral administration of 150 mg clomipramine, the mean elimination half-life of clomipramine is 32 hours (range: 19–37 hours), and the mean elimination half-life of desmethylclomipramine is 69 hours (range: 54–77 hours). Due to the saturation of pharmacokinetics, the elimination half-life can vary significantly at different doses.
After a single oral administration of 150 mg clomipramine, its mean elimination half-life is approximately 32 hours (range: 19–37 hours), and the mean elimination half-life of desmethylclomipramine is approximately 69 hours (range: 54–77 hours).
This study aimed to determine the pharmacokinetics of clomipramine and its major metabolite (desmethylclomipramine) in canine plasma after a single intravenous or oral administration of clomipramine. The subjects were 6 male and 6 female beagle dogs. Three administration methods were used: intravenous injection (2 mg/kg), oral administration after a 15-hour fast (4 mg/kg), and oral administration within 25 minutes of feeding (4 mg/kg). …The elimination half-life of clomipramine after intravenous administration was 5 hours… This study aimed to determine the plasma pharmacokinetics of dogs after single and multiple oral administrations of different doses of clomipramine and its major metabolite (desmethylclomipramine). … Three male and three female dogs were given clomipramine orally at doses of 1, 2, or 4 mg/kg, initially as a single dose, followed by twice-daily administration for 10 consecutive days after a 14-day interval. …After repeated administration, the terminal half-life increased slightly (1.6-fold for clomipramine and 1.2-fold for desmethylclomipramine), but the terminal half-life was short in all groups (≤4 hours).

Toxicity Summary
Clomipramine is a potent but not entirely selective serotonin reuptake inhibitor (SRI) because its main active metabolite, desmethylclomipramine, primarily inhibits the reuptake of norepinephrine. Alpha-1 receptor blockade and β-receptor downregulation have been observed, which likely play a role in the short-term effects of clomipramine. As with other tricyclic antidepressants, the blocking of sodium channels and NDMA receptors may explain its efficacy in treating chronic pain, particularly neuropathic pain. Interactions Limited data suggest that long-term alcohol consumption may reduce the demethylating effect of clomipramine. One study found significantly reduced demethylated clearance of clomipramine in patients who had recently abstained from alcohol (4–20 weeks of abstinence), and the steady-state ratio of serum clomipramine to desmethylclomipramine concentrations was higher in patients with a higher risk than in controls without a history of alcohol abuse.
It has been reported that clomipramine plasma concentrations increase with concomitant use of haloperidol; plasma concentrations of several structurally related tricyclic antidepressants increase with concomitant use of methylphenidate or liver enzyme inhibitors (e.g., cimetidine, fluoxetine), and decrease with concomitant use of liver enzyme inducers (e.g., barbiturates, phenytoin sodium), and clomipramine is expected to produce similar effects. It has also been reported that clomipramine, when used in combination with phenobarbital, increases phenobarbital plasma concentrations.
It has been reported that many tricyclic antidepressants can block the pharmacological effects of guanethidine, clonidine, or similar drugs; due to the structural similarity of clomipramine to other tricyclic antidepressants, clomipramine is expected to produce similar effects.
Close monitoring and careful dose adjustment are necessary when clomipramine is used in combination with anticholinergic or sympathomimetic drugs.
For complete data on more drug interactions of clomipramine (11 in total), please visit the HSDB record page.

[1]. The tricyclic antidepressant Clomipramine increases plasma glucose levels of mice. J Pharmacol Sci. 2003 Sep;93(1):74-9.

[2]. Comparative study of the inhibitory effect of antidepressants on cholinesterase activity in Bungarus sindanus (krait) venom, human serum and rat striatum. J Enzyme Inhib Med Chem. 2008 Dec;23(6):912-7.

[3]. The tricyclic antidepressant Clomipramine inhibits neuronal autophagic flux. Sci Rep. 2019 Mar 19;9(1):4881.

Therapeutic Uses
Tricyclic antidepressant; serotonin reuptake inhibitor. Clomipramine hydrochloride capsules are indicated for the treatment of obsessive thoughts and compulsive behaviors in patients with obsessive-compulsive disorder (OCD). These obsessive thoughts or compulsive behaviors must cause significant distress, consume time, or severely interfere with social or occupational functioning to meet the diagnostic criteria for OCD in DSM-III-R (circa 1989). /US Product Label Includes/ /Veterinary Treatment/ A prospective, randomized, double-blind, placebo-controlled, parallel-group, international multicenter clinical trial tested the efficacy and tolerability of clomipramine in the treatment of separation anxiety in dogs. To diagnose separation anxiety, a dog must exhibit at least one of the following symptoms in the absence of its owner: destruction of objects, defecation, urination, and/or barking, and exhibiting “excessive attachment” to its owner. Ninety-five dogs were randomly assigned to receive one of three treatment regimens for 2–3 months: standard-dose clomipramine (1 to <2 mg/kg, orally, every 12 hours); low-dose clomipramine (0.5 to <1 mg/kg, orally, every 12 hours); and placebo (orally, every 12 hours). All dogs received behavioral therapy. Dogs were examined at four time points after the start of treatment (days 0, 28, 56, and 84). Behavioral improvement was assessed for each dog on days 28, 56, and 84 and compared with behavior on day 0. Results showed that dogs receiving standard-dose clomipramine improved at least three times faster in destructive behavior, defecation, and urination compared to the placebo group. At most time points, the standard-dose clomipramine group showed greater improvement in destructive behavior, defecation, and urination, as well as better overall owner assessments of the dog's behavior than the placebo group (p<0.05 at some time points). However, at any time point, there was no statistically significant difference in vocalization between the standard-dose group and the placebo group. The low-dose clomipramine group did not produce a statistically significant effect compared to the placebo group. A small number of dogs experienced mild and transient vomiting after taking clomipramine. The conclusion is that adding a standard dose (1–<2 mg/kg, orally, every 12 hours) of clomipramine to routine behavioral therapy for 2–3 months can improve separation anxiety symptoms in dogs.

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Drug Warning
/Black Box Warning/ Suicidal Tendency and Antidepressants: Short-term studies have shown that antidepressants increase the risk of suicidal ideation and behavior (suicidal tendency) in children, adolescents, and young adults compared to placebo. Anyone considering the use of clomipramine or other antidepressants in children, adolescents, or young adults must weigh this risk against clinical need. Short-term studies have shown that in adults aged 24 years and older, taking antidepressants did not increase the risk of suicide compared to taking a placebo; in adults aged 65 years and older, taking antidepressants decreased the risk of suicide compared to taking a placebo. Depression and some other mental illnesses are themselves associated with an increased risk of suicide. Patients of all ages starting antidepressants should be appropriately monitored for worsening clinical symptoms, suicidal ideation, or unusual behavioral changes. Family members and caregivers should be informed of the need for close monitoring and communication with the prescribing physician. Clomipramine hydrochloride capsules are not approved for use in children, except for those with obsessive-compulsive disorder (OCD). Adults and children with major depressive disorder or other mental illnesses may experience exacerbations of depressive symptoms and/or suicidal ideation and behavior (suicidal tendencies) or unusual behavioral changes, regardless of whether they are taking antidepressants. This risk may persist until clinically meaningful remission is achieved. Suicide is a known risk factor for depression and some other mental illnesses, which are themselves the strongest predictors of suicide. However, there has long been concern that antidepressants may induce exacerbations of depression and suicidal tendencies in some patients during the early stages of treatment. A pooled analysis of short-term, placebo-controlled studies of antidepressants (e.g., selective serotonin reuptake inhibitors and other antidepressants) showed an increased risk of suicide in children, adolescents, and young adults (18–24 years) with major depressive disorder and other mental illnesses. In adults 24 years and older, antidepressants did not show an increased risk of suicide compared to placebo, while a decreased risk was observed in adults 65 years and older. It is unclear whether this risk persists with long-term use (i.e., beyond several months). However, substantial evidence from placebo-controlled maintenance treatment trials in adults with major depressive disorder suggests that antidepressants can delay relapse of depression. The FDA's pooled analysis showed differences in suicide risk across different mental illness indications, with the highest incidence observed in major depressive disorder studies. …The average risk of such events in children and adolescents taking these medications was 4%, twice that of the placebo group (2%). …Furthermore, although the risk varied considerably among different antidepressants, almost all study medications showed a trend toward increased suicide risk in younger patients. It is unclear whether this risk in pediatric patients persists with long-term use (e.g., beyond several months). Based on this analysis and public discussion on this issue, the FDA has instructed all antidepressant manufacturers to add a boxed warning to their product labels to alert clinicians to the suicide risk associated with children and adolescents taking these medications, and to recommend appropriate monitoring and close observation of patients taking these medications. This revised labeling covers all antidepressants, including those that have not yet undergone controlled clinical trials in pediatric patients, as existing data are insufficient to rule out any single antidepressant increasing suicide risk. In addition to the boxed warning and other information on the antidepressant label, the FDA now recommends providing patients with a medication guide explaining the risks associated with the medication each time it is dispensed. More complete data on clomipramine (57 in total) warnings can be found on the HSDB record page. Pharmacodynamics: Clomipramine is a tricyclic antidepressant, a 3-chloro derivative of imipramine. It was previously thought that the mechanism of action of tricyclic antidepressants was simply the inhibition of the reuptake of neurotransmitters such as norepinephrine and serotonin by nerve cells. However, while the effect is immediate, mood improvement takes about two weeks. It is now believed that changes occur in the sensitivity of receptors in the cerebral cortex and hippocampus. The hippocampus is part of the limbic system, the part of the brain associated with mood. Presynaptic receptors are affected: α1 and β1 receptors are sensitized, and α2 receptors are desensitized (leading to increased norepinephrine production). Tricyclic antidepressants are also considered effective analgesics for treating various types of pain, particularly neuropathic pain or neuralgia. Clomipramine hydrochloride (G34586) is a tricyclic antidepressant (TCA) primarily approved for the treatment of obsessive-compulsive disorder (OCD) and major depressive disorder (MDD), characterized by its potent inhibition of serotonin (5-HT) reuptake [1,3].
- Mechanism of hyperglycemia: Its hyperglycemic effect in vivo is attributed to decreased insulin sensitivity in peripheral tissues (e.g., skeletal muscle) and potential inhibition of insulin signaling pathways, although its exact molecular targets (e.g., IRS-1, AKT) have not been investigated in the relevant literature [1].
- Significance of autophagy inhibition: The inhibition of neuronal autophagy mediated by clomipramine hydrochloride (G34586) may contribute to its therapeutic effect in neurodegenerative diseases (off-label use). The potential mechanism of action is through reducing abnormal protein aggregation, but this needs further verification [3].
- Relevance of cholinesterase inhibition: Its cholinesterase inhibitory activity may explain the anticholinergic side effects (e.g., dry mouth, constipation) observed in clinical applications, because AChE inhibition increases synaptic acetylcholine levels [2].

C19H24CL2N2

351.31

350.131

C, 64.96; H, 6.89; Cl, 20.18; N, 7.97

17321-77-6

Clomipramine-d3 hydrochloride; 1398065-86-5; Clomipramine; 303-49-1; Clomipramine-d3; 136765-29-2; Clomipramine-d6 hydrochloride; 1189882-28-7; Clomipramine-13C,d3 hydrochloride

2801

White to off-white crystalline powder

434.2ºC at 760 mmHg

189-190°C

216.4ºC

9.63E-08mmHg at 25°C

5.395

0

2

4

22

346

0

ClC1C([H])=C([H])C2C([H])([H])C([H])([H])C3=C([H])C([H])=C([H])C([H])=C3N(C=2C=1[H])C([H])([H])C([H])([H])C([H])([H])N(C([H])([H])[H])C([H])([H])[H].Cl[H]

WIMWMKZEIBHDTH-UHFFFAOYSA-N

InChI=1S/C19H23ClN2.ClH/c1-21(2)12-5-13-22-18-7-4-3-6-15(18)8-9-16-10-11-17(20)14-19(16)22;/h3-4,6-7,10-11,14H,5,8-9,12-13H2,1-2H3;1H

3-(2-chloro-5,6-dihydrobenzo[b][1]benzazepin-11-yl)-N,N-dimethylpropan-1-amine;hydrochloride

Clomimipramine; G 34586; 3-Chloroimipramine; G-34586; G34586; Trade names: Anafranil, Clomicalm

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 3 mg/mL (8.54 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 30.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 3 mg/mL (8.54 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 30.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 3 mg/mL (8.54 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 30.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 100 mg/mL (284.65 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)