Clomipramine

Synthetic Routes and Reaction Conditions: Clomipramine is synthesized through a multi-step process starting from iminodibenzyl. The key steps involve:

Chlorination: Iminodibenzyl is chlorinated to form 3-chloroiminodibenzyl.

Reduction: The chlorinated product is reduced to 3-chloro-10,11-dihydro-5H-dibenzo[b,f]azepine.

Alkylation: The final step involves alkylation with 3-dimethylaminopropyl chloride to yield this compound.

Industrial Production Methods: Industrial production of this compound typically follows the same synthetic route but on a larger scale. The process involves stringent control of reaction conditions to ensure high purity and yield. The final product is often converted to its hydrochloride salt form for stability and ease of formulation .

Metabolic Reactions of Clomipramine

This compound undergoes extensive hepatic metabolism, primarily mediated by cytochrome P450 enzymes :

Phase I Metabolism

Phase II Metabolism

• Glucuronidation : Conjugation of hydroxylated metabolites (e.g., 8-hydroxythis compound) via UDP-glucuronosyltransferases (UGTs) .

Elimination :

• Urinary excretion : 51–60% as metabolites .

• Fecal excretion : 24–32% via biliary elimination .

Key Pharmacokinetic Data

Metabolic Saturation : Nonlinear kinetics observed at higher doses due to CYP2D6 polymorphism .

Degradation and Stability

This compound hydrochloride is stable under standard storage conditions but degrades under extreme pH or UV exposure. Key degradation products include:

• Hydrolysis : Formation of iminostilbene derivatives in acidic/basic conditions.

• Oxidation : N-oxide derivatives under oxidative stress .

Enzymatic Interactions

This compound inhibits or induces several enzymes:

• CYP2D6 Inhibition : Alters metabolism of co-administered drugs (e.g., codeine) .

• hERG Channel Blockade : Binds to cardiac potassium channels (K~i~ = 130 nM), contributing to arrhythmia risk .

Comparative Reactivity Table

Structural Insights

• Molecular Formula : C₁₉H₂₃ClN₂ .

• Key Functional Groups :

  • Tricyclic dibenzazepine core.

  • Chlorine substituent at position 3.

  • Dimethylaminopropyl side chain .

FDA-Approved Indications

The primary FDA-approved indication for clomipramine is the treatment of obsessive-compulsive disorder in patients aged 10 years and older. It was the first medication specifically approved for OCD, receiving this designation in 1989. A meta-analysis indicated that this compound significantly improved symptoms as measured by the Children's Yale-Brown Obsessive-Compulsive Scale, outperforming other selective serotonin reuptake inhibitors such as sertraline and fluoxetine .

Off-Label Uses

This compound has several off-label uses, which include:

• Depression: Effective in treating major depressive disorder, particularly when other treatments have failed.
• Anxiety Disorders: Utilized for generalized anxiety disorder and panic disorder.
• Chronic Pain Management: Shows efficacy in neuropathic pain conditions.
• Insomnia: Sometimes prescribed for sleep disturbances due to its sedative effects.
• Body Dysmorphic Disorder: Assists in reducing obsessive thoughts about perceived flaws.
• Trichotillomania: Helps manage compulsive hair-pulling behaviors.
• Premature Ejaculation: Occasionally used to delay ejaculation in men .

Case Study: this compound in OCD Treatment

A comprehensive study involving children and adolescents with OCD demonstrated that this compound led to a 37% improvement in OCD symptoms compared to baseline measurements. This study highlighted this compound's effectiveness relative to other SSRIs, reinforcing its role as a viable option for treatment-resistant cases .

Research on COVID-19

Recent investigations have explored this compound's potential as an antiviral agent against SARS-CoV-2. A study indicated that this compound significantly reduced ACE2 internalization, thereby inhibiting viral entry into cells. When administered prior to infection, it demonstrated a 91% reduction in intracellular viral RNA levels, suggesting a promising avenue for repurposing this medication for COVID-19 treatment .

Data Table: Summary of this compound Applications

クロミプラミンは、中枢神経系におけるセロトニンとノルエピネフリンの再取り込みを阻害することによって作用します。これにより、シナプス間隙におけるこれらの神経伝達物質の濃度が上昇し、神経伝達の強化につながります。 この化合物は、ヒスタミン-H1受容体、α1アドレナリン受容体、およびムスカリン受容体も遮断するため、鎮静作用、降圧作用、抗コリン作用に寄与します .

類似化合物:

イミプラミン: 同様の適応症で使用される別の三環系抗うつ薬です。

アミトリプチリン: 鎮静作用で知られており、うつ病と慢性疼痛の治療に使用されます。

ノルトリプチリン: 異なる副作用プロファイルを持つ二次アミン三環系抗うつ薬.

クロミプラミンの独自性: クロミプラミンは、他の三環系抗うつ薬と比較して、セロトニン再取り込みを強力に阻害するという点でユニークです。これは、強迫性障害の治療に特に効果的です。 さらに、その代謝物である脱メチルクロミプラミンは、ノルエピネフリン再取り込みを選択的に阻害するため、二重の作用機序を提供します .

Imipramine: Another tricyclic antidepressant used for similar indications.

Amitriptyline: Known for its sedative properties and used in the treatment of depression and chronic pain.

Nortriptyline: A secondary amine tricyclic antidepressant with a different side effect profile.

Uniqueness of Clomipramine: this compound is unique due to its strong inhibition of serotonin reuptake compared to other tricyclic antidepressants. This makes it particularly effective in treating obsessive-compulsive disorder. Additionally, its metabolite, desmethylthis compound, preferentially inhibits norepinephrine reuptake, providing a dual mechanism of action .

Clomipramine is a tricyclic antidepressant (TCA) primarily used in the treatment of obsessive-compulsive disorder (OCD) and depression. Its biological activity extends beyond mere serotonin reuptake inhibition, influencing various biological pathways and mechanisms. This article delves into the compound's pharmacodynamics, mechanisms of action, efficacy in clinical settings, and recent research findings.

This compound's primary mechanism involves the inhibition of serotonin and norepinephrine reuptake. However, it also exhibits several other biological activities:

• GTPase Activity Inhibition : Recent studies have shown that this compound inhibits the GTPase activity of dynamin isoforms (Dyn1, Dyn2, Dyn3), which play a crucial role in clathrin-mediated endocytosis. This inhibition may have implications for reducing viral entry, including SARS-CoV-2 .

  Dynamin Isoform	IC50 Value (μM)
  Dyn1	22.0 ± 2.2
  Dyn2	12.8 ± 3.2
  Dyn3	11.3 ± 2.9

• Anticholinergic Effects : this compound exhibits anticholinergic properties, which can lead to side effects such as dry mouth and constipation but may also contribute to its therapeutic effects in some patients .
• Impact on Neurotransmitter Systems : Besides serotonin and norepinephrine, this compound also affects dopamine receptors, which may enhance its efficacy in treating OCD by modulating dopaminergic pathways .

Treatment of Obsessive-Compulsive Disorder

This compound has been extensively studied for its efficacy in treating OCD:

• Double-Blind Studies : Two significant double-blind studies involving over 500 patients demonstrated that this compound significantly reduced obsessive and compulsive symptoms compared to placebo, with mean reductions of 38% and 44% on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) .
• Intravenous Administration : A controlled study indicated that intravenous this compound led to faster symptom improvement compared to oral administration, with a mean Y-BOCS score reduction of approximately 30% at discharge .

Case Studies

• Case Study on Treatment-Resistant OCD : A study involving patients who did not respond to traditional treatments found that intravenous this compound resulted in significant symptom reduction (mean Y-BOCS score dropped from 27.9 to 18.10) over a follow-up period .
• Post-COVID-19 Symptoms : A recent trial is investigating the efficacy of this compound for managing post-COVID-19 symptoms, highlighting its potential versatility beyond psychiatric disorders .

Side Effects and Tolerability

This compound is generally well tolerated; however, common side effects include:

• Sedation
• Weight Gain
• Anticholinergic Effects : Such as dry mouth and constipation
• Seizures : Though rare, seizures can occur, particularly at higher doses .

Basic Research Questions

Q. What experimental models are suitable for assessing clomipramine's neurotoxic or neuroprotective effects in vitro?

To evaluate this compound's neurotoxic or neuroprotective properties, researchers commonly use in vitro neuronal models such as mouse P19-derived neurons. Key methodologies include:

• MTT reduction assays to measure mitochondrial activity and cell viability.
• LDH release assays to quantify membrane integrity and cytotoxicity.
• Dose-response curves (e.g., 1–100 µM this compound) to establish concentration-dependent effects .
  Standard protocols require triplicate experiments and statistical validation (e.g., ANOVA with post hoc tests) to ensure reproducibility.

Q. How can researchers determine therapeutic versus toxic concentrations of this compound in preclinical studies?

• Plasma concentration monitoring : Compare clinically effective serum levels (e.g., 150–450 ng/mL in depression) with toxic thresholds (>500 ng/mL).
• Tissue-specific analysis : Postmortem studies use liquid chromatography-mass spectrometry (LC-MS) to quantify this compound and its metabolite northis compound in brain, liver, and blood, accounting for postmortem redistribution artifacts .
• In vitro cytotoxicity assays : Establish IC50 values for neuronal viability (e.g., P19 neurons show significant toxicity at ≥50 µM) .

Q. What pharmacokinetic factors must be considered when studying this compound in elderly populations?

• Reduced metabolic clearance : Hepatic CYP450 enzyme activity declines with age, leading to elevated plasma levels.
• Drug-drug interactions : this compound inhibits CYP2D6 and CYP2C19, affecting co-administered medications.
• Dose adjustment : Start with 30–50% of adult doses and titrate based on therapeutic drug monitoring (TDM) .

Advanced Research Questions

Q. How can researchers reconcile contradictions between this compound's preclinical neurotoxicity and its clinical safety profile?

• Species and model disparities : Rodent models (e.g., P19 neurons) may overestimate human neurotoxicity due to metabolic differences.
• Dose translation : Preclinical studies often use supratherapeutic concentrations (e.g., ≥50 µM), exceeding clinical plasma levels.
• Long-term safety data : Retrospective cohort studies in elderly populations show this compound’s cardiac risks (QT prolongation) require ECG monitoring, but mutagenicity/carcinogenicity studies report no significant concerns .

Q. What experimental designs are optimal for evaluating this compound as an augmenting agent in SSRI-resistant OCD?

• Sequential addition trials : Randomize SSRI non-responders to this compound augmentation (25–75 mg/day) versus placebo, using the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) for symptom tracking .
• Pharmacodynamic synergy : Assess serotonin transporter (SERT) occupancy via PET imaging to differentiate this compound’s dual serotonin/norepinephrine reuptake inhibition from SSRIs.
• Safety endpoints : Monitor anticholinergic effects (e.g., dry mouth, constipation) and cardiac parameters (e.g., QTc interval) .

Q. How can researchers address the paucity of tissue distribution data for this compound in forensic toxicology?

• Postmortem LC-MS protocols : Quantify this compound/northis compound in brain, liver, and blood to distinguish acute toxicity from chronic use.
• Case-control comparisons : Compare tissue levels in fatal overdoses (e.g., brain >5 µg/g) versus therapeutic doses, adjusting for postmortem redistribution .

Q. What statistical frameworks are critical for analyzing this compound’s early response patterns in pediatric OCD trials?

• Mixed-effects models : Analyze weekly CY-BOCS scores to identify early responders (≥75% improvement by Week 2) versus late responders.
• Time-to-event analysis : Use Kaplan-Meier curves to compare response trajectories between this compound and SSRIs, adjusting for placebo effects .

Q. Methodological Guidelines

• Data validation : Replicate findings across independent cohorts and control for confounders (e.g., CYP2D6 polymorphisms affecting this compound metabolism).
• Ethical reporting : Disclose funding sources, adverse event rates, and attrition biases in clinical trials .
• Systematic reviews : Follow PRISMA guidelines to minimize selection bias in meta-analyses .