Clomipramine

Serotonin Transporter (SERT) Affinity and Inhibition

This compound exhibits a high affinity for the serotonin transporter (SERT). patsnap.comnih.govontosight.ai This high affinity leads to potent inhibition of serotonin reuptake into the presynaptic neuron, increasing the availability of serotonin in the synaptic space. patsnap.comontosight.ai Studies have shown that this compound has a significantly higher preference in affinity for SERT compared to the norepinephrine transporter (NET). wikipedia.org Positron emission tomography (PET) studies in humans have demonstrated that this compound can produce substantial occupancy of SERT even at relatively low plasma concentrations. psychotropical.com For instance, a plasma concentration of 1.42 ng/mL has been shown to result in approximately 80% occupancy of SERT in humans. psychotropical.com

Note: Ki values can vary depending on the specific study and methodology used. caymanchem.commedchemexpress.combiocrick.com

Norepinephrine Transporter (NET) Affinity and Inhibition

Note: Ki values can vary depending on the specific study and methodology used. wikipedia.orgcaymanchem.commedchemexpress.com

Dopamine Transporter (DAT) Indirect Modulation

This compound's primary action is on SERT and NET. patsnap.comwikipedia.orgontosight.ai While it has shown some affinity for the dopamine transporter (DAT), this affinity is considerably lower than its affinity for SERT and NET. wikipedia.orgcaymanchem.com Some sources indicate a weak or modest affinity for dopamine receptors D2 and D3. pharmgkb.org The modulation of dopaminergic neurotransmission by this compound is considered to be less direct compared to its effects on serotonin and norepinephrine reuptake. ontosight.ai

Note: Ki/Kd values can vary depending on the specific study and methodology used. wikipedia.orgcaymanchem.com

Histamine H1 Receptor Antagonism

This compound has a high affinity for the histamine H1 receptor and acts as an antagonist at this site. nih.govpharmgkb.orgnih.gov This antagonism is a common property among tricyclic antidepressants and is thought to contribute to effects such as sedation. nih.govpatsnap.comwikipedia.orgontosight.ai

Note: Kd values can vary depending on the specific study and methodology used. caymanchem.comguidetopharmacology.org

Alpha-1 Adrenergic Receptor Antagonism

This compound also acts as an antagonist at alpha-1 adrenergic receptors. nih.govwikipedia.orgpharmgkb.orgnih.gov This antagonism is associated with certain physiological effects. nih.govpatsnap.comwikipedia.org

Note: Kd values can vary depending on the specific study and methodology used. caymanchem.com

Compound Names and PubChem CIDs

Note: PubChem CIDs are provided for the mentioned compounds.

Muscarinic Acetylcholine Receptor Antagonism

This compound acts as an antagonist at muscarinic acetylcholine receptors (mAChRs). wikipedia.orgcaymanchem.com This antagonism is thought to contribute to some of the side effects associated with TCAs, such as dry mouth, constipation, blurred vision, and cognitive impairment. wikipedia.org There are five subtypes of muscarinic receptors (M1-M5), and this compound has been shown to antagonize M1 receptors, among others. wikipedia.orgcaymanchem.comwikipedia.org Chronic inhibition of cholinergic receptors by TCAs is believed to be a major mechanism underlying withdrawal symptoms upon discontinuation, potentially due to a rebound effect of excessive cholinergic activity. wikipedia.org

Serotonin Receptor Subtype Affinities (e.g., 5-HT2A, 5-HT2C, 5-HT3A)

Beyond its primary action on the serotonin transporter (SERT), this compound also demonstrates affinity for various serotonin receptor subtypes, acting as an antagonist at several of them. wikipedia.org Specifically, this compound has been identified as an antagonist at the 5-HT2A, 5-HT2C, 5-HT3, 5-HT6, and 5-HT7 receptors. wikipedia.org The 5-HT2 receptor family, including 5-HT2A and 5-HT2C, are predominantly expressed in peripheral tissues but are also found in the central nervous system. webaigo.it 5-HT2A and 5-HT2C receptors are implicated in mediating the neurochemical and behavioral effects of psychostimulants. webaigo.it The 5-HT3 receptor is unique among monoamine receptors as it is a ligand-gated ion channel. ihs-headache.orgcsic.es Blockade of 5-HT3 receptors can augment the increase in serotonin levels caused by SERT inhibition. csic.es Antagonism of 5-HT2A/2C receptors has been suggested to improve the antidepressant action of selective serotonin reuptake inhibitors (SSRIs). csic.es

Dopamine Receptor Subtype Affinities (e.g., D2, D3)

This compound also exhibits activity at dopamine receptors, acting as an antagonist at D1, D2, and D3 receptors. wikipedia.org Dopamine receptors are categorized into two families: D1-like (D1 and D5) and D2-like (D2, D3, and D4). medchemexpress.com D2 and D3 receptors are part of the D2-like family. medchemexpress.com D3 receptors are particularly concentrated in limbic areas, including the nucleus accumbens, and are associated with cognitive, emotional, and endocrine functions. nih.govacnp.org Antagonism of D2 and D3 receptors by this compound may partially explain its efficacy in treating obsessive-compulsive disorder (OCD). nih.gov Chronic antidepressant treatment, including TCAs, can lead to increased responsiveness of postsynaptic D2/D3 receptors in the mesolimbic system. acnp.org

Here is a table summarizing some reported receptor affinities for this compound:

Note: Affinity values (Ki or Kd) represent the binding strength of the compound to the receptor, with lower values indicating higher affinity. Different studies may report varying values depending on methodology.

Presynaptic Receptor Desensitization (e.g., 5-HT1A, Beta-adrenergic)

Chronic administration of antidepressants, including this compound, can lead to the desensitization of presynaptic autoreceptors, such as the serotonin 5-HT1A and beta-adrenergic receptors. cambridge.orgcambridge.orgmedscape.com Presynaptic 5-HT1A autoreceptors are located on the cell bodies and dendrites of serotonergic neurons and initially inhibit neuronal firing and serotonin release when activated by increased synaptic serotonin. nih.govplos.orgnih.gov Chronic treatment leads to the downregulation or desensitization of these autoreceptors, allowing for increased firing of serotonergic neurons and greater serotonin release in projection areas. nih.govplos.org Similarly, this compound presumably increases noradrenergic neurotransmission by blocking the norepinephrine reuptake pump, which is thought to result in the desensitization of beta-adrenergic receptors. cambridge.orgcambridge.org This desensitization process is considered to contribute to the delayed onset of the full therapeutic effects of TCAs and SSRIs. nih.gov

Impact on Neurotrophic Factors (e.g., BDNF)

Neurotrophic factors, particularly brain-derived neurotrophic factor (BDNF), play a crucial role in neuronal survival, growth, and plasticity, and are implicated in the pathophysiology of depression. mdpi.comfrontiersin.orgnih.gov Chronic antidepressant treatment has been shown to increase BDNF availability and expression in brain regions like the hippocampus and cortex. mdpi.comfrontiersin.orgresearchgate.net Studies in animal models have demonstrated that chronic this compound treatment can restore reduced levels of glial cell line-derived neurotrophic factor (GDNF), another neurotrophic factor, in the hippocampus. frontiersin.orgresearchgate.net This suggests that modulation of neurotrophic factors like BDNF and GDNF may be involved in the behavioral responses to antidepressants. researchgate.net Antidepressants can increase the production of BDNF and GDNF in the rat hippocampus. researchgate.net While the exact mechanisms are still being elucidated, increased monoamine levels due to reuptake inhibition may contribute to BDNF release, and antidepressants may also activate BDNF signaling pathways independently. mdpi.com

Influence on Cellular Homeostasis and Autophagy

Autophagy is a fundamental cellular process crucial for maintaining homeostasis by degrading and recycling damaged organelles and misfolded proteins frontiersin.org. This process is vital for cellular health and adaptation to stress frontiersin.orgmdpi.com. Studies indicate that this compound can influence this critical pathway.

Research suggests that this compound interferes with autophagic flux, potentially impacting the degradation and recycling of cellular components researchgate.netfrontiersin.orgoncotarget.comnih.gov. Specifically, studies have shown that this compound can block the fusion of autophagosomes with lysosomes, a late stage in the autophagic process oncotarget.commdpi.com. This blockage leads to an accumulation of autophagosomal markers, such as LC3-II and p62, which are typically degraded during functional autophagy researchgate.netoncotarget.comnih.gov.

Studies in primary dissociated neurons have demonstrated that this compound can undermine autophagosome formation and cargo degradation researchgate.netnih.gov. Similar observations were made in the frontal cortex and liver of treated mice, as well as in Caenorhabditis elegans exposed to the compound researchgate.netnih.gov. These findings suggest that this compound may negatively regulate autophagic flux across various tissues, potentially having implications for the homeostatic maintenance of differentiated cells researchgate.netnih.gov.

The active metabolite of this compound, desmethylthis compound (northis compound), has also been shown to interfere with autophagic flux by increasing LC3-II levels while blocking the degradation of autophagic cargo oncotarget.commdpi.comnih.gov. This interference with lysosomal degradation by desmethylthis compound further supports the notion that this compound and its metabolite impact the later stages of autophagy oncotarget.comnih.gov.

While the exact mechanisms by which this compound influences autophagy are still being elucidated, the observed interference with autophagosome-lysosome fusion and the accumulation of autophagic markers highlight its impact on this crucial cellular homeostatic process oncotarget.commdpi.comnih.gov.

Anti-inflammatory Properties and Mechanisms

Beyond its effects on monoamine transporters and cellular homeostasis, this compound has demonstrated significant anti-inflammatory properties in various experimental models nih.govtandfonline.comnih.govtandfonline.comnih.goveajm.orgresearchgate.net. These effects are observed both peripherally and within the central nervous system (CNS) nih.govnih.govfrontiersin.org.

In studies using cells isolated from human blood, this compound has been shown to suppress the production of pro-inflammatory cytokines by T cells and monocytes, while increasing the production of the anti-inflammatory cytokine IL-10 nih.govfrontiersin.org. Specifically, this compound has been reported to reduce the production of IL-1β, IL-6, TNFα, IFNγ, and IL-2 by monocytes and T lymphocytes nih.gov. The reduction in pro-inflammatory cytokine production by T cells is partially explained by this compound's inhibition of T-cell proliferation nih.govfrontiersin.org.

Studies in microglial cells, the primary immune cells in the CNS, have shown that this compound decreases the production of TNFα and nitric oxide (NO) in response to inflammatory stimuli like lipopolysaccharide (LPS) nih.govnih.govfrontiersin.org. It also reduces the mRNA expression of inducible nitric oxide synthase (iNOS), IL-1β, and TNFα nih.govnih.govfrontiersin.org. Furthermore, this compound has been shown to inhibit the activation of key pro-inflammatory pathways, including NF-κB and p38 MAPK, in microglial cells nih.govnih.gov. These findings are particularly relevant as microglia and astrocytes are central mediators of neuroinflammation nih.govnih.govfrontiersin.org.

This compound's anti-inflammatory effects extend to in vivo models of inflammation. In rat models of carrageenan-induced paw edema, this compound has been shown to decrease inflammation and inflammatory exudate nih.govtandfonline.comtandfonline.comnih.govresearchgate.net. In LPS-induced inflammation models, this compound demonstrated an immunomodulatory effect, decreasing TNF-α and increasing TGF-β1 after repeated administration, and increasing IL-10 after a single dose tandfonline.comtandfonline.comnih.gov.

One proposed mechanism for this compound's anti-inflammatory action involves the inhibition of the NLRP3 inflammasome nih.govnih.govresearchgate.netmdpi.com. The NLRP3 inflammasome is a multiprotein complex that plays a crucial role in the inflammatory response by processing pro-inflammatory cytokines like IL-1β and IL-18 into their active forms researchgate.netmdpi.com. Inhibition of the NLRP3 inflammasome by this compound leads to a significant decrease in the levels and gene expression of IL-1β and IL-6, as well as TNFα nih.govnih.gov.

Another potential mechanism contributing to this compound's anti-inflammatory effects is its influence on serotonin levels. Increased extracellular serotonin levels have been reported to decrease TNFα and IL-6 production nih.gov. This compound, by inhibiting serotonin reuptake, increases extracellular serotonin, which may contribute to its anti-inflammatory profile nih.govtandfonline.com.

This compound has also been shown to modulate human glucocorticoid receptor function, which could partly explain its anti-inflammatory effects nih.gov. Furthermore, studies suggest that this compound can interfere with the activity of inflammatory mediators such as histamine, serotonin, and bradykinin, and may reduce neutrophil migration and stabilize mast cells researchgate.netscielo.br.

The consistent demonstration of anti-inflammatory properties across various in vitro and in vivo studies highlights a significant neurobiological mechanism of this compound that extends beyond its well-established role in monoamine reuptake inhibition nih.govtandfonline.comnih.govtandfonline.comnih.goveajm.orgresearchgate.net.

Table 1: Summary of this compound's Influence on Cytokine Levels in Inflammatory Models

Table 2: this compound's Influence on Inflammatory Pathways and Cells

Formation and Activity of Desmethylthis compound (Active Metabolite)

Genetic Variations in Pharmacodynamic Genes (e.g., SLC6A4/5-HTTLPR) and Therapeutic Response

Genetic variations in pharmacodynamic genes, particularly those involved in neurotransmitter systems, can influence the therapeutic response to this compound. The serotonin transporter gene, SLC6A4 (also known as 5-HTT), which encodes the serotonin transporter, is one such gene that has been investigated. medscape.comelsevier.es A key polymorphism in the promoter region of SLC6A4 is the 44-base-pair insertion/deletion polymorphism, known as 5-HTTLPR. pharmgkb.orgmedscape.comelsevier.es This polymorphism has been shown to influence gene expression, with the long (L) allele generally associated with higher transcriptional activity compared to the short (S) allele. medscape.comelsevier.es

Studies exploring the association between the 5-HTTLPR polymorphism and this compound response have yielded inconsistent results. medscape.comscielo.br Some research suggests that subjects with the homozygous deletion (S/S) genotype may exhibit a poorer therapeutic response to this compound, based on observations of greater this compound-induced prolactin release in healthy subjects with the insertion (L) allele. pharmgkb.orgmedscape.com However, other studies in patients with OCD have not found a significant association between response to this compound and genetic variation in SLC6A4. pharmgkb.org The inconsistency in findings may be attributed to factors such as small sample sizes, heterogeneity in pharmacological treatment, and variations in OCD phenotypes across studies. medscape.com The functional triallelic nature of the 5-HTTLPR polymorphism (L-allele with A [LA], G substitution [LG], and S), where the LG variant shows expression levels comparable to the S-allele, has also not been consistently considered, further complicating comparisons of previous findings. medscape.com

Beyond SLC6A4, other genes in the serotonin system have also been examined, though studies are limited. medscape.com Variants in genes such as FKBP5 and ABCB1 have been identified as potential genetic predictors for increased risk of suicidal ideation in patients taking antidepressant medication, including this compound, highlighting the complex interplay of genetic factors and treatment outcomes. pharmgkb.org

Efficacy in Reducing OCD Symptoms (e.g., Y-BOCS scores)

Clinical trials have consistently shown this compound's effectiveness in reducing the severity of OCD symptoms, as measured by standardized scales such as the Yale-Brown Obsessive Compulsive Scale (Y-BOCS). tandfonline.comnih.govcambridge.org A significant reduction in Y-BOCS scores, typically defined as a decrease of at least 25% to 35% from baseline, is considered an adequate treatment response in clinical trials. tandfonline.comnih.govuspharmacist.com

Studies have demonstrated statistically significant reductions in Y-BOCS scores with this compound treatment. For instance, in one open trial evaluating intravenous this compound for treatment-resistant OCD, the mean Y-BOCS score dropped from a severe range (24–31) at admission to a moderate range (16–23) at discharge and follow-ups. nih.gov Specifically, the mean score at discharge was 18.10, representing a 30.74% reduction, and this improvement was maintained at 24 weeks with a mean score of 16.32 (36.81% reduction). nih.gov In another multicenter study involving children and adolescents with OCD, a 37% improvement in the Children's Yale–Brown Obsessive–Compulsive Scale (CY-BOCS) score was recorded with this compound compared to placebo. cambridge.org

Data from various studies highlight the significant impact of this compound on Y-BOCS scores:

Long-term Efficacy and Remission Rates in OCD

Long-term studies on this compound in OCD have been limited. While this compound can confer protection against relapse as long as it is continued, naturalistic follow-up studies of patients maintained on serotonergic antidepressants, including this compound, show high rates of remission, implying a continued anti-obsessional property. tandfonline.com

However, long-term OCD studies have revealed a low remission rate. One study noted a 20% remission rate at 40 years. nih.gov Another perspective suggests that 40% to 60% of patients treated with serotonin reuptake inhibitors (SRIs), including this compound, respond to treatment, but only a portion achieve remission. nih.gov Remission criteria in studies have varied, ranging from a Y-BOCS score < 16 to a score ≤ 7. cambridge.org A score of 16 is generally considered too high for true remission, while a score of 7 may be too low to be achieved by a sufficient number of patients to be meaningful in studies. cambridge.org

A follow-up study of patients identified as having treatment-refractory OCD, who were initially treated with intravenous this compound, examined long-term outcomes 4 to 11 years later. psychiatryonline.org Among the patients for whom data was obtained, 46% reported being subjectively clinically better compared to study entry, and 30% no longer met criteria for OCD. psychiatryonline.org However, none reported full remission. psychiatryonline.org

A small double-blind study examining response to long-term maintenance medication in patients successfully treated with serotonergic antidepressants (this compound or fluvoxamine) for at least 10 weeks found that 70% to 90% of patients maintained treatment gains after 102 days, even with dose reduction in some groups. jwatch.org This provides preliminary support for lower-dose maintenance therapy in stabilized patients with an excellent acute response. jwatch.org

Intravenous this compound in Treatment-Resistant Cases

Intravenous administration of this compound has been explored as an option for severe and treatment-resistant OCD cases that have not adequately responded to oral therapies, including oral this compound. nih.govpsychiatryonline.org The rationale for intravenous administration includes potentially achieving higher plasma and brain levels compared to oral dosing, which may lead to a more rapid or pronounced response. jwatch.org

Several studies have investigated the efficacy of intravenous this compound in TR-OCD. A placebo-controlled study demonstrated that intravenous this compound was superior to intravenous placebo in patients who were previously refractory to oral this compound. psychiatryonline.org An open trial found that intravenous this compound led to clinically and statistically significant reductions in Y-BOCS scores in poor responders to previous multiple trials of anti-obsessive medications. nih.gov At discharge, a significant percentage of patients showed a ≥ 25% decrease in Y-BOCS scores, and a notable proportion were still responders at 24 weeks. nih.gov

A pilot double-blind, placebo-controlled study comparing intravenous versus oral this compound pulse-loading treatment reported a significant response shortly after the second infusion. stanford.edu An open-label study suggested a faster response onset for intravenous pulse-loaded treatment compared to gradual oral dosing. stanford.edu

While promising results have been reported for intravenous this compound in TR-OCD, further controlled trials comparing this approach to other evidence-based strategies, such as augmentation with dopamine-blocking medications or psychotherapy, are needed to clarify its precise role in the treatment algorithm for TR-OCD. stanford.edu

Efficacy in Major Depressive Disorder and Treatment-Resistant Depression

This compound is employed in the treatment of major depressive disorder (MDD) and is a common off-label treatment in the United States, while holding approved status in countries such as Australia, the United Kingdom, and Japan for this indication. wikipedia.org Some evidence suggests that this compound may possess superior efficacy compared to other antidepressants in treating MDD, particularly in more severe presentations, although current data may not definitively substantiate this claim. wikipedia.org this compound has been established as a treatment for depressive illness, notably in cases of treatment-resistant depression (TRD). droracle.ai Its effectiveness in managing both depression and resistant depression has been demonstrated. droracle.ai

A pilot study investigating a single pulse dose of intravenous this compound in inpatients with moderate to severe depression revealed a significant amelioration of depressive symptoms within one week. isciii.es This treatment approach, involving a single intravenous pulse dose followed by oral administration, led to a notable decrease of 39% ± 22% in Montgomery Asberg Rating Scale (MADRS) scores and a 28% ± 19% decrease in Clinical Global Impression (CGI) scores within one week, with both improvements reaching statistical significance. isciii.es Research into this compound augmentation in patients who had not responded to prior MAO inhibitor or fluoxetine therapy indicated marginal efficacy when compared to augmentation with a conventional TCA. nih.gov

Combinational Approaches (e.g., with Lithium, Tryptophan)

The efficacy of this compound in treating resistant depression may be enhanced through combination therapy, such as with tryptophan and/or lithium. droracle.ai The successful use of a combination regimen including this compound, L-tryptophan, and lithium has been documented in seven case studies involving patients with severe endogenous depression who had not responded to previous treatments. nih.gov Reports on the successful application of lithium/clomipramine and L-tryptophan/clomipramine combination therapy in two obsessive patients who continued to exhibit symptoms after this compound monotherapy support the hypothesis that augmenting serotonergic neurotransmission can help alleviate obsessive symptoms. psychiatryonline.org Augmentation with lithium and tryptophan has been explored in cases of this compound-resistant obsessive-compulsive disorder, with observed improvement lending support to the serotonergic neurotransmission hypothesis. nih.gov The combination of a MAO inhibitor or an SSRI with a TCA has also shown value in the management of treatment-resistant depression. nih.gov

Panic Disorder and Agoraphobia

This compound is utilized in the treatment of panic disorder and agoraphobia. wikipedia.org Studies have shown that in patients diagnosed with panic disorder, with or without agoraphobia, this compound effectively reduces the frequency and severity of panic attacks within 7 to 21 days of initiating treatment, and this efficacy is sustained for at least 12 months. nih.gov this compound has demonstrated greater effectiveness than imipramine after two weeks of treatment for panic disorder, although their efficacy appears similar after 6 or 10 weeks. nih.gov Double-blind studies have indicated that this compound is more effective than placebo and at least as effective as fluvoxamine and oxitriptan (5-hydroxytryptophan) in decreasing panic attacks and associated anxiety. nih.gov

A placebo-controlled study comparing aerobic exercise, this compound, and placebo in patients with panic disorder found that both exercise and this compound resulted in a significant reduction of symptoms compared to placebo. psychiatryonline.org A direct comparison within this study revealed that this compound led to a significantly earlier and more effective improvement in anxiety symptoms than exercise. psychiatryonline.org In a 12-week placebo-controlled study evaluating paroxetine, this compound, and cognitive therapy for panic disorder with or without agoraphobia, this compound consistently demonstrated superiority over pill placebo. psychiatrist.com An 8-week open trial involving seventeen outpatients with panic anxiety and agoraphobia treated with low-dose this compound reported complete cessation of panic attacks in 13 patients and a marked decrease in the remaining individuals. researchgate.net Avoidance behavior resolved in five out of the seven agoraphobic patients in this trial. researchgate.net

Generalized Anxiety Disorder

This compound is used in the treatment of generalized anxiety disorder. wikipedia.org Preliminary evidence supporting the use of this compound for generalized anxiety disorder comes from a small open-label trial. psychiatryonline.orgscite.ai In a 12-week double-blind, randomized, placebo-controlled trial involving children and adolescents with anxiety disorders, including GAD, this compound showed comparable efficacy to fluoxetine, although it did not demonstrate superiority over placebo. nih.govresearchgate.net All treatment groups in this study, including this compound, fluoxetine, and placebo, exhibited significant improvement. nih.govresearchgate.net

Cataplexy Syndrome

This compound has been notably used to treat cataplexy associated with narcolepsy wikipedia.org. Cataplexy, a symptom of narcolepsy, involves sudden episodes of muscle tone loss often triggered by strong emotions dovepress.com. Research indicates that this compound can reduce the propensity for cataplexy attacks nih.gov.

Studies, including self-report assessments, have shown a reduction in the propensity to cataplexy with this compound treatment nih.gov. Early research involving patients with narcolepsy and cataplexy demonstrated that this compound could abolish cataplexy in some individuals and reduce attack frequency in others psu.edu. The anticataplectic effect of this compound is thought to be related to its influence on cerebral amine metabolism psu.edu. While this compound has been used for many years for cataplexy, often based on case reports and small open-label studies, larger, more formal randomized, placebo-controlled clinical trials specifically evaluating this compound for cataplexy have been noted as lacking in some reviews dovepress.com. However, some earlier controlled trials did investigate its effects. For instance, one study compared fluvoxamine and this compound in subjects with narcolepsy and cataplexy, finding that both drugs improved cataplexy, though fluvoxamine was less active nih.gov. Another early report indicated that this compound in doses of 25 to 75 mg/day completely stopped attacks of cataplexy, sleep paralysis, and hypnagogic hallucinations within 48 hours in a small group of patients researchgate.net.

Off-Label Uses and Emerging Research Areas

In addition to its approved indication for OCD, this compound is utilized off-label for a range of other conditions nih.govwikipedia.orgmentalhealth.com. These off-label uses include major depressive disorder, panic disorder, trichotillomania, body dysmorphic disorder, and chronic pain nih.govwikipedia.org. It has also been used for hyperacusis and premature ejaculation wikipedia.org.

Emerging research areas and off-label applications highlight the broader impact of this compound's pharmacological profile. Its use in treating depression and anxiety is documented, with some evidence suggesting effectiveness in panic disorder nih.govmentalhealth.com. This compound has also shown benefit in reducing the severity of trichotillomania compared to placebo in some studies nih.gov. Research has also explored its use in chronic pain conditions, including tension headaches nih.govwikipedia.org.

Double-Blind, Placebo-Controlled Trial Designs

Double-blind, placebo-controlled trial designs are considered a cornerstone for establishing the efficacy of a treatment researchgate.netisciii.es. In such trials, neither the participants nor the researchers are aware of whether the participant is receiving the active drug or a placebo, minimizing bias researchgate.netpsychiatryonline.org. Several studies investigating this compound, particularly for OCD, have employed this design researchgate.netpsychiatryonline.orgresearchgate.net. For example, a randomized, double-blind, placebo-controlled trial compared this compound, exposure and ritual prevention, and their combination in treating adult outpatients with OCD researchgate.netpsychiatryonline.org. Another study used a double-blind, placebo-controlled crossover design to assess this compound in depressed patients with Alzheimer's disease psychiatryonline.org. These designs help to isolate the effect of the medication from placebo response and other confounding factors.

Outcome Measures and Their Validation

The selection and validation of appropriate outcome measures are critical for accurately assessing treatment effects in clinical trials researchgate.netisciii.es. For conditions like OCD, standardized scales such as the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) are commonly used to quantify symptom severity researchgate.netpsychiatryonline.orgcambridge.org. Response rates, often determined by scales like the Clinical Global Impression (CGI) improvement scale, are also frequently used outcome measures researchgate.netpsychiatryonline.org.

Validation of these outcome measures ensures that they accurately reflect the constructs they are intended to measure and are sensitive to changes resulting from treatment researchgate.net. In studies evaluating this compound for OCD, the Y-BOCS total score and CGI improvement scale have been primary outcome measures researchgate.netpsychiatryonline.org. For other conditions, different validated scales specific to those disorders would be employed. For instance, studies on depression might use scales like the Hamilton Depression Rating Scale (HDRS) or Montgomery Asberg Rating Scale (MADRS) isciii.espsychiatryonline.org.

Addressing Publication Bias in Efficacy Research

Researchers employ various methods to assess and address publication bias. Funnel plots are a graphical tool used to visually inspect for potential publication bias; asymmetry in a funnel plot can suggest bias nih.govfrontiersin.org. Statistical methods, such as Egger's test, can also be used to formally test for funnel plot asymmetry psychiatryonline.orgfrontiersin.org. Some meta-analyses evaluating pharmacotherapies, including this compound, for conditions like OCD have examined for publication bias psychiatryonline.orgresearchgate.net. While some analyses have found indications of publication bias in the literature on OCD pharmacotherapy, others focusing on specific subsets of studies, such as NIH-funded trials of psychological treatments for OCD, have suggested an absence of such bias in that specific area researchgate.netresearchgate.net. Addressing publication bias is important for providing a more accurate and unbiased estimate of this compound's true effect size across different indications researchgate.net.

Increased Risk of Suicidality in Specific Populations

Pooled analyses of short-term, placebo-controlled trials of antidepressant drugs, including clomipramine, have indicated an increased risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (up to 24 years of age) with major depressive disorder and other psychiatric disorders. nih.govmedlineplus.govfda.gov This risk appears to be highest during the initial weeks of treatment and following dosage adjustments. medlineplus.gov In contrast, short-term studies have not demonstrated a significant increase in suicidality risk in adults over 24, and some evidence suggests a reduced risk in adults aged 65 and older. nih.govfda.gov It is important to note that depression and other psychiatric disorders themselves are associated with an elevated risk of suicide. nih.govfda.gov Research emphasizes the need for close monitoring of patients in these age groups for clinical worsening, suicidality, or unusual behavioral changes when initiating antidepressant therapy. nih.govfda.gov

Seizures and Convulsant Properties

This compound has been associated with seizures, and its convulsant properties are a known adverse effect in research settings. wikipedia.orgnih.govdusunenadamdergisi.org The risk of seizures with this compound is considered higher compared to some other antidepressants. wikipedia.org Research in specific populations, such as adults with pervasive developmental disorders (PDDs), has reported seizures during this compound treatment. In one open-label investigation involving 35 adults with PDDs, three patients experienced seizures, including two with a prior history of seizure disorders who were also taking anticonvulsants. nih.gov Among the 32 patients without a history of prior seizures, one experienced a seizure during the study. nih.gov This highlights that while a history of seizures increases the risk, seizures can also occur in individuals without such a history. Careful monitoring for seizures is warranted in research involving this compound, particularly in vulnerable populations. nih.gov

Serotonin Syndrome Risk and Mechanisms

Serotonin syndrome is a potentially serious adverse effect that can occur with this compound, particularly when combined with other serotonergic agents. patsnap.comnih.govuspharmacist.compsychiatry-psychopharmacology.comcambridge.org this compound's primary mechanism of action involves potent inhibition of serotonin reuptake, leading to increased extracellular serotonin concentrations in the synaptic cleft. wikipedia.orgpatsnap.com Serotonin syndrome is characterized by excessive serotonergic activity in the central nervous system. psychiatry-psychopharmacology.comcambridge.org While it typically results from interactions between two or more drugs that elevate serotonin levels through different mechanisms, it can also occur with a single agent. uspharmacist.com this compound, due to its high serotonergic activity, contributes to this risk. patsnap.comuspharmacist.com The interaction with monoamine oxidase inhibitors (MAOIs) is a classic example of a drug combination that can precipitate severe serotonin syndrome. psychiatry-psychopharmacology.comcambridge.org Research underscores the importance of carefully monitoring for signs and symptoms of serotonin syndrome when this compound is used, especially in combination with other medications affecting serotonergic systems. patsnap.compsychiatry-psychopharmacology.comcambridge.org

Extrapyramidal Side Effects (e.g., Dystonia, Akathisia, Dyskinesia)

Extrapyramidal side effects (EPS), including dystonia, akathisia, and dyskinesia, have been reported in research involving this compound. dusunenadamdergisi.orgfishersci.cajcdr.net While often associated with antipsychotic medications due to their dopamine D2 receptor blockade, TCAs like this compound can also induce EPS. dusunenadamdergisi.orgjcdr.net Proposed mechanisms include the inhibition of dopaminergic function in the nigrostriatal pathway, an imbalance between dopaminergic, serotonergic, noradrenergic, or cholinergic activity, and serotonergic inhibition of dopaminergic functions in the striatum. dusunenadamdergisi.orgajphs.com Research indicates that extrapyramidal side effects with TCAs can be dose-dependent and may resolve with dose reduction or discontinuation of the drug. dusunenadamdergisi.org A review of studies examining EPS related to cyclic antidepressants reported occurrences of akathisia in 26% of TCA users, dystonia in 17%, and reversible dyskinesia in 52%. dusunenadamdergisi.orgjcdr.netdusunenadamdergisi.org Although the number of reported cases of acute dystonia specifically with this compound may be low, it is a recognized potential adverse effect. dusunenadamdergisi.orgajphs.comdusunenadamdergisi.org

Mania Induction

Research has observed the induction of mania or hypomania in some patients treated with this compound, particularly in individuals with unipolar depression. nih.govsemanticscholar.orgnih.govhres.ca In a study comparing this compound and amitriptyline in hospitalized unipolar depressed patients, six out of 25 patients treated with this compound developed manic behavior, compared to only one patient in the amitriptyline group. nih.gov This suggests a potential link between this compound and the precipitation of mania in susceptible individuals. nih.gov The mechanism underlying this compound-induced mania is not fully understood but is hypothesized to involve alterations in central dopamine and serotonin systems, potentially related to a hyper-serotonergic state. semanticscholar.orgnih.gov Case reports also document instances of this compound-induced mania in patients with obsessive-compulsive disorder. semanticscholar.orgresearchgate.net Researchers emphasize the importance of monitoring for manic symptoms in patients receiving this compound. semanticscholar.org

Cognitive Impairment

Cognitive impairment has been investigated in the context of this compound use. nih.govresearchgate.netnih.gov this compound's anticholinergic activity is thought to contribute to certain cognitive side effects, such as memory impairment. wikipedia.orgresearchgate.net Research examining the effects of chronic this compound use in patients with panic disorder found associations between longer-term treatment and poorer performance on implicit memory tests, as well as between higher serum levels of this compound or its metabolite, desmethylthis compound, and lower performance in central executive tests and metamemory. researchgate.net These findings suggest that chronic this compound administration, even at low doses, may be associated with diminished metamemory and impaired priming and working memory. researchgate.net Preclinical studies in rodents also indicate that this compound may negatively affect hippocampus-dependent spatial learning and memory. nih.gov However, the effects in humans require further conclusive epidemiological evidence. nih.gov Some research also explores the potential for psychotropic medications, including antidepressants, to influence cognitive decline in neurodegenerative disorders, although findings in this area are not always consistent. nih.govfrontiersin.org

Potential Data Table (Illustrative - based on search results, actual data points may vary across studies):

Note: The data presented in this table is a summary of findings from various research sources and should be interpreted in the context of the specific study designs and populations. Interactive data tables would allow for filtering, sorting, and potentially visualizing data from multiple studies.

Cardiac Arrhythmias, QTc Prolongation, and Conduction Disorders

Liver Enzyme Elevation and Potential Liver Injury

Inhibitors of CYP1A2, CYP2C19, CYP3A4, and CYP2D6 and this compound Levels

Concomitant administration of drugs that inhibit CYP enzymes involved in this compound metabolism can lead to increased plasma concentrations of this compound and its active metabolite. Inhibitors of CYP2D6, such as fluoxetine, paroxetine, sertraline, quinidine, and cimetidine, can increase this compound levels, particularly in poor metabolizers. pharmgkb.orgpsychiatrist.comnih.gove-lactancia.org For instance, fluoxetine can significantly increase the levels of coadministered tricyclic antidepressants. psychiatrist.com Fluvoxamine, a potent inhibitor of CYP1A2 and CYP2C19, and also inhibiting CYP2D6 and CYP3A4, can lead to substantial increases in this compound concentrations. psychiatrist.come-lactancia.org Studies have shown that co-administration of fluvoxamine can increase steady-state serum levels of this compound approximately 4-fold. e-lactancia.org Ciprofloxacin, a CYP1A2 inhibitor, can also increase this compound levels. medscape.com Clarithromycin and dronedarone, which inhibit CYP3A4, can increase this compound levels. medscape.com Terbinafine, a strong inhibitor of CYP2D6, may also increase exposure to this compound and its metabolite, potentially necessitating dose adjustments. e-lactancia.org Haloperidol has also been reported to increase plasma concentrations of this compound. fda.govrxlist.com

Inducers of Hepatic Enzymes and this compound Levels

Conversely, drugs that induce hepatic enzymes, particularly CYP3A4, CYP2C19, and CYP1A2, can accelerate the metabolism of this compound, leading to decreased plasma concentrations and potentially reduced efficacy. hres.cae-lactancia.org Known inducers of CYP3A and CYP2C, such as rifampicin and anticonvulsants like barbiturates, carbamazepine, phenobarbital, and phenytoin, may decrease this compound concentrations. hres.cae-lactancia.orgfda.govrxlist.com CYP1A2 inducers, such as components in cigarette smoke (nicotine), can also decrease plasma concentrations of tricyclic drugs like this compound. e-lactancia.orgfda.gov Studies have shown that in cigarette smokers, this compound steady-state plasma concentrations were decreased 2-fold compared to non-smokers. e-lactancia.org Lonapegsomatropin will decrease the level or effect of this compound by affecting hepatic enzyme CYP1A2 metabolism. medscape.com

Serotonergic Agents and Serotonin Syndrome Risk

This compound is a potent inhibitor of serotonin reuptake, and its concomitant use with other serotonergic agents can increase the risk of serotonin syndrome. medsafe.govt.nzwikipedia.orgdrugbank.com Serotonin syndrome is a potentially life-threatening condition resulting from excessive serotonergic activity in the central nervous system. wikipedia.orgnih.govnih.gov Symptoms can range from mild (e.g., high blood pressure, fast heart rate) to severe (e.g., hyperthermia, agitation, rigidity, seizures, coma). medsafe.govt.nzwikipedia.org

The risk of serotonin syndrome is particularly high when this compound is combined with:

Monoamine oxidase inhibitors (MAOIs): Concomitant use is contraindicated due to the potential for severe interactions, including hypertensive crisis, hyperpyrexia, and serotonin syndrome. nih.govrxlist.commedicinesinformation.co.nzmedsafe.govt.nz A washout period of at least 14 days is required when switching between this compound and MAOIs. nih.govrxlist.commedicinesinformation.co.nzmedsafe.govt.nz

Selective serotonin reuptake inhibitors (SSRIs): SSRIs like fluoxetine, paroxetine, sertraline, and fluvoxamine can have additive serotonergic effects with this compound. e-lactancia.orgmedsafe.govt.nzwikipedia.org

Other serotonergic agents: This includes tramadol, pethidine, dextromethorphan, fentanyl, lithium, buspirone, tryptophan, and St. John's Wort. medsafe.govt.nzwikipedia.orgdrugs.comdrugs.com Some opioids, such as tramadol and meperidine, possess serotonergic activity and can precipitate serotonin syndrome in conjunction with other serotonergic medication. ukclinicalpharmacy.orgdrugs.com Triptans also carry a risk of serotonin syndrome when used with this compound. wikipedia.orgdrugs.com Methylthioninium chloride (methylene blue) should be avoided in patients taking serotonergic drugs like this compound due to the risk of serotonin syndrome. ukclinicalpharmacy.org

If serotonin syndrome is suspected, all serotonergic agents should be discontinued, and supportive care initiated. drugs.comdrugs.com

Other CNS Depressants

This compound has central nervous system (CNS) depressant effects, and concomitant use with other CNS depressants can result in additive effects, leading to increased sedation, respiratory depression, coma, and potentially death. fda.govdrugs.commedsafe.govt.nzdrugs.com Caution is advised when using this compound with substances such as alcohol, barbiturates, benzodiazepines, general anesthetics, opioids, and antipsychotics. fda.govukclinicalpharmacy.orgmedsafe.govt.nzdrugs.com The combination of this compound with alcohol can lead to additive impairment of motor skills. drugs.com Concomitant use with opioids may also result in increased sedation and impaired judgment. drugs.com

Highly Protein-Bound Drugs

This compound is approximately 97% protein-bound, primarily to albumin. nih.govdrugs.com Co-administration of this compound with other highly protein-bound drugs, such as warfarin or digoxin, may lead to increased plasma concentrations of these other drugs due to displacement from protein binding sites, potentially resulting in adverse effects. nih.govdrugs.com Conversely, this compound levels could potentially decrease if displaced by other highly protein-bound drugs, although this interaction has not been fully evaluated. nih.govdrugs.com While some tricyclic antidepressants may potentiate the anticoagulant effect of coumarin drugs like warfarin, there is no specific evidence for this compound inhibiting the metabolism of anticoagulants like warfarin; however, careful monitoring of plasma prothrombin is advised. e-lactancia.orgmedicinesinformation.co.nz

QTc Prolonging Agents

This compound, a tricyclic antidepressant, is recognized as an agent that can prolong the QTc interval. ementalhealth.caggcmedicines.org.ukukclinicalpharmacy.org Prolongation of the QTc interval is associated with an increased risk of serious ventricular arrhythmias, including torsade de pointes, which can potentially lead to sudden cardiac death. ggcmedicines.org.ukdrugs.com The risk of QTc prolongation and subsequent arrhythmias is generally unpredictable but can be heightened by certain underlying factors such as congenital long QT syndrome, existing cardiac disease, and electrolyte imbalances, particularly hypokalemia and hypomagnesemia. ementalhealth.cadrugs.comdrugs.com

The risk of QTc prolongation with this compound is considered notable, and this risk is amplified when co-administered with other medications known to prolong the QTc interval. ggcmedicines.org.ukukclinicalpharmacy.org This additive effect increases the potential for ventricular arrhythmias. drugs.com Many drug interaction resources advise avoiding or using alternate drugs when combining this compound with other QTc prolonging agents. medscape.com

Examples of drugs that may increase the risk of QTc prolongation when combined with this compound include certain antipsychotics (such as haloperidol, chlorpromazine, thioridazine, amisulpride), antiarrhythmics (like amiodarone, quinidine, sotalol, disopyramide), some antibiotics (erythromycin, clarithromycin, moxifloxacin, ciprofloxacin), antifungals (ketoconazole, fluconazole), antimalarials (hydroxychloroquine, chloroquine, mefloquine, artemether/lumefantrine), and other antidepressants (including some SSRIs like citalopram and escitalopram, as well as other TCAs like imipramine, amitriptyline, doxepin, maprotiline, lofepramine, amoxapine, and trimipramine). ementalhealth.caggcmedicines.org.ukukclinicalpharmacy.orgdrugs.commedscape.comdrugbank.comnih.gov The extent of QTc prolongation is often dose-dependent for individual drugs and combinations. ggcmedicines.org.ukdrugs.com

Monitoring of the QTc interval via electrocardiogram (ECG) is recommended at baseline and after achieving the desired clinical effect when using this compound, especially when co-administered with other QTc-prolonging agents. psychiatrist.comnih.gov Close clinical monitoring for signs and symptoms that could indicate torsade de pointes, such as dizziness, lightheadedness, fainting, palpitations, irregular heart rhythm, shortness of breath, or syncope, is also advised. drugs.com

Clomipramine in Animal Models of Depression

Animal models of depression often assess behavioral despair and anhedonia. The forced swim test (FST) and tail suspension test (TST) are commonly used paradigms to evaluate antidepressant-like activity by measuring immobility time, which is interpreted as behavioral despair nih.govconductscience.comnih.gov. A decrease in immobility time is considered indicative of potential antidepressant effects.

Studies have investigated the effects of this compound in the forced swim test in mice and rats. In some instances, this compound has been shown to reduce immobility time in the FST, suggesting antidepressant-like effects nih.govnih.gov. However, the effectiveness can vary depending on factors such as the animal strain, sex, and the specific experimental protocol, including whether a pre-test session is used nih.gov. For example, one study in rats found that chronic treatment with this compound was effective in the FST only in high novelty seeking male rats and low novelty seeker female rats nih.gov. Another study using neonatal this compound administration in rats, hypothesized to create an animal model of depression, found that adult rats treated neonatally with this compound had significantly fewer offensive fighting responses and significantly more defensive fighting responses in a shock-induced fighting test, which the authors suggest adds support to the validity of this depression model nih.gov. However, in the same neonatal this compound model, adult treatment with imipramine did not alter immobility in the forced swim test, questioning the generalizability of this neonatal this compound model for depression and the validity of the FST in this specific context researchgate.net.

In the tail suspension test, which also measures immobility as an indicator of depressive-like behavior, this compound has been studied in mice. Preferential serotonin re-uptake blockers, including this compound, were reported to be poorly active in non-reserpinized mice and inactive in reserpine-treated mice in the tail suspension test nih.gov.

A chronic social defeat stress model in male mice, which induces a mixed anxiety/depression state, was used to study this compound's effects. This compound at a dose of 40 mg/kg decreased communicativeness in the partition test, produced anxiogenic effects, decreased exploratory activity in the plus-maze test, and had an antidepressive effect in the Porsolt's test (forced swim test) eco-vector.com.

Another study using a variable frequency ultrasound model of depression in rats found that this compound treatment reduced immobility time in the forced swim test compared to the control group mdpi.com. This study also observed differences in the purine metabolic pathway in rats treated with intraperitoneal this compound mdpi.com.

This compound in Animal Models of Anxiety and PTSD

Animal models of anxiety often utilize tests such as the elevated plus maze (EPM) and marble burying test. The EPM measures anxiety-like behavior based on an animal's aversion to open spaces, while the marble burying test assesses compulsive-like digging behavior, which can be interpreted in the context of anxiety or OCD.

In the chronic social defeat stress model in male mice, this compound at 40 mg/kg produced anxiogenic effects and decreased exploratory activity in the plus-maze test eco-vector.com.

A study using neonatal this compound exposure in rats, intended to model OCD-like behaviors, also reported enhanced anxiety in adulthood as measured by the elevated plus maze and marble burying test capes.gov.brdovepress.com. In the marble burying test, this compound-exposed rats buried more foreign/novel objects dovepress.com.

Research specifically on this compound in animal models of PTSD was not prominently found in the provided search results. The available information primarily focuses on depression and OCD models, with some overlap into anxiety.

This compound in Animal Models of Obsessive-Compulsive Disorder

Animal models of OCD aim to capture repetitive or compulsive-like behaviors. These models include pharmacologically induced behaviors and neurodevelopmental manipulations.

Repeated administration of the dopamine D2 agonist quinpirole is one pharmacological model that induces compulsive checking behavior in rodents, which has been shown to be partially attenuated by chronic administration of this compound, supporting the predictive validity of this model dovepress.comnih.govcas.cz.

Another approach involves neonatal administration of this compound to induce long-lasting behavioral changes. Neonatal exposure to this compound in rats between postnatal days 9 and 16 has been reported to produce multiple symptoms consistent with an OCD-like profile in adulthood capes.gov.brdovepress.com. These behavioral changes included enhanced anxiety in the elevated plus maze and marble burying tests, behavioral inflexibility (perseveration in the spontaneous alternation task and impaired reversal learning), working memory impairment, and hoarding capes.gov.brdovepress.com. These behavioral alterations were accompanied by biochemical changes, such as elevated dopamine D2 receptors in the striatum and elevated serotonin 2C receptors in the orbital frontal cortex capes.gov.brdovepress.com. However, one study using repeated adolescent injection of this compound in combination with a behavioral paradigm designed to produce compulsive lever pressing failed to exacerbate this behavior nih.gov.

Studies also suggest that animal models of OCD, including those responsive to this compound, indicate a role for serotonin and dopamine neurotransmitters, particularly 5-HT2c and D1/D2 receptors, in the pathology of the disorder .

Neurotransmitter Transporter Binding Assays

This compound is a tricyclic antidepressant that primarily inhibits the reuptake of serotonin (5-HT) and norepinephrine (NE) by blocking their respective transporters, SERT and NET wikipedia.orgnih.govpatsnap.comdrugbank.comhres.ca. This action increases the concentration of these neurotransmitters in the synaptic cleft, enhancing neurotransmission wikipedia.orgnih.govpatsnap.com.

This compound exhibits a higher affinity for the serotonin transporter (SERT) compared to the norepinephrine transporter (NET) wikipedia.orgnih.govpatsnap.com. Its major active metabolite, desmethylthis compound (northis compound), also plays a significant role, binding to the NET with very high affinity and having dramatically reduced affinity for the SERT wikipedia.org. Desmethylthis compound circulates at concentrations approximately twice those of this compound wikipedia.org. This contributes to this compound's classification as a fairly balanced SNRI despite the parent drug's preference for SERT wikipedia.org.

In vitro studies using techniques like neurotransmitter transporter binding assays are used to quantify the affinity of this compound and its metabolites for these transporters. While specific detailed data tables from binding assays were not extensively provided in the search results, the literature consistently describes this compound as a potent inhibitor of serotonin reuptake and desmethylthis compound as a potent inhibitor of norepinephrine reuptake wikipedia.orgnih.govpatsnap.comdrugbank.compharmgkb.org. Positron emission tomography (PET) studies in humans and non-human primates have shown occupancy of both SERT and NET with this compound administration, supporting the in vitro findings and the combined effect of the parent drug and its metabolite wikipedia.orgresearchgate.netnih.gov. PET studies indicate that even low doses of this compound can produce substantial occupancy of the human serotonin transporter psychotropical.com.

This compound has also been described as a potent modulator of the dopamine transporter (DAT), exhibiting unique electrostatic interactions with the binding site scbt.com. However, compared to its effects on SERT and NET, its affinity for DAT is generally considered lower wikipedia.org.

Receptor Binding and Functional Assays

Beyond its primary action on neurotransmitter transporters, this compound also interacts with a variety of receptors. In vitro studies using receptor binding and functional assays help characterize these interactions and their potential implications.

This compound has affinity for several receptors, including alpha1-adrenergic, histamine H1, and muscarinic acetylcholine receptors wikipedia.orgpatsnap.compharmgkb.org. It is an antagonist at these receptors wikipedia.orgpatsnap.compharmgkb.org. Specifically, it has demonstrated high affinity for histamine receptor H1 and cholinergic receptor, muscarinic 1 in animal studies pharmgkb.org. It is also reported to be an antagonist of serotonin 5-HT2A, 5-HT2C, 5-HT3, 5-HT6, and 5-HT7 receptors, and dopamine D1, D2, and D3 receptors wikipedia.org.

In vitro studies have shown that this compound can modulate glucocorticoid receptor (GR) function. One study found that this compound decreased glucocorticoid inhibition of LPS-stimulated IL-6 levels in diluted whole blood cells from healthy controls, but this effect was not observed in treatment-resistant depressed patients nih.gov. This suggests a potential interaction between this compound and the hypothalamic-pituitary-adrenal (HPA) axis, which is often dysregulated in depression pharmgkb.org.

Behavioral, electrophysiological, and microdialysis studies suggest that serotonin receptors, particularly 5-HT1A, 5-HT1B, and 5-HT2C subtypes, play a key role in modulating this compound activity scielo.br. Indirect activation of neurotransmitter receptors by this compound, via increased endogenous serotonin levels, may also influence G protein-coupled receptors, signal transduction, transcription factors, and neurotrophic factors like brain-derived neurotrophic factor scielo.br.

While detailed quantitative data from a comprehensive range of receptor binding and functional assays were not consistently available across the search results, the literature indicates that this compound interacts with a broad spectrum of receptors in addition to its primary targets, the serotonin and norepinephrine transporters.

Cellular Mechanisms of Anti-inflammatory Effects

Research indicates that this compound possesses anti-inflammatory properties through several cellular mechanisms. Studies have shown that this compound can modulate the production of cytokines by immune cells. For instance, in cells isolated from human blood samples, this compound was found to suppress the production of pro-inflammatory cytokines like interferon-gamma (IFNγ) by T cells and interleukin-1 beta (IL-1β) by monocytes, while increasing the production of the anti-inflammatory cytokine IL-10. nih.gov This reduction in pro-inflammatory cytokines was partly attributed to this compound's inhibition of T-cell proliferation. nih.gov

Furthermore, studies on microglial cells, which are key mediators of neuroinflammation in the central nervous system (CNS), have demonstrated that this compound can decrease the production of inflammatory mediators. In microglial cells co-cultured with neurons and stimulated with lipopolysaccharides (LPS) to induce inflammation, this compound at therapeutic concentrations reduced the production of tumor necrosis factor-alpha (TNFα) and nitric oxide. nih.gov It also decreased the mRNA expression of inducible nitric oxide synthase, IL-1β, and TNFα, and attenuated the activation of NF-κB and p38 MAPK pathways, leading to reduced cell death. nih.gov

An in vitro and in vivo study highlighted that this compound can inhibit the NLRP3 inflammasome, a multiprotein complex involved in the inflammatory response. nih.govnih.gov This inhibition led to a significant decrease in the levels and gene expression of pro-inflammatory cytokines such as TNFα, IL-1β, and IL-6. nih.govnih.gov This effect on the NLRP3 inflammasome in microglia appears to be partially involved in this compound's ability to attenuate depressive behaviors and neuroinflammation induced by LPS in mice. nih.gov

This compound has also been shown to attenuate the inflammatory response by inhibiting neutrophil migration and mast cell degranulation. scielo.brscielo.brresearchgate.net Studies in rats demonstrated that this compound significantly counteracted the chemotactic response of neutrophils and inhibited compound 48/80-induced mast cell degranulation. scielo.brscielo.brresearchgate.net

The anti-inflammatory effects of this compound may also be linked to its influence on serotonin levels, as high extracellular levels of serotonin have been reported to decrease TNFα and IL-6 production. nih.gov Additionally, this compound might modulate human glucocorticoid receptor function, which could partly explain its anti-inflammatory properties. nih.gov

Studies on Autophagic Flux in Neuronal Cells

Research indicates that this compound interferes with autophagic flux, a cellular process involving the degradation and recycling of damaged organelles and proteins. Early observations noted the appearance of autophagy-associated structures in the cytoplasm of cells treated with this compound. frontiersin.orgfrontiersin.org Subsequent studies, employing methods to assess autophagic flux, demonstrated that this compound and its active metabolite, desmethylthis compound (CID 9731), interfere with this process, effectively blocking functional autophagy. frontiersin.orgfrontiersin.orgoncotarget.com

Studies in primary cultured neuronal cells have shown that this compound negatively regulates the neuronal autophagic pathway. medchemexpress.commedchemexpress.com this compound at concentrations of 1 and 5 µM enhanced the conversion of LC3-I to LC3-II in a concentration-dependent manner over time, indicating an accumulation of autophagosomes, a hallmark of blocked autophagic flux. medchemexpress.comresearchgate.netresearchgate.net This interference with autophagic flux by this compound and desmethylthis compound is also revealed by an increase in authophagosomal markers and a concomitant blockade of the degradation of autophagic cargo, such as p62. oncotarget.com

In vivo studies in mice treated with this compound (20 mg/kg) have also shown a decrease in autophagic flux in tissues, including the liver, with significant increases in both LC3-II and p62 levels compared to vehicle-treated mice. medchemexpress.commedchemexpress.com A similar pattern was observed in the frontal cortex of treated mice and in the nematode Caenorhabditis elegans exposed to this compound. researchgate.net These findings suggest that this compound may negatively regulate autophagic flux in various tissues. researchgate.net

Here is a summary of selected findings on this compound's effect on autophagic flux in neuronal cells:

Neuroprotective Potential (e.g., Multiple Sclerosis)

Studies suggest that this compound may possess neuroprotective properties, particularly in the context of neurodegenerative diseases like Multiple Sclerosis (MS). Research in animal models of MS, specifically experimental autoimmune encephalomyelitis (EAE), has shown that this compound can ameliorate clinical signs of the disease in both acute and chronic phases. multiplesclerosisnewstoday.comnih.gov This neuroprotective effect is thought to involve the reduction of inflammation and microglial activation, as well as the preservation of axonal integrity. nih.gov A systematic screening of generic drugs for progressive MS identified this compound as a promising therapeutic candidate due to its capacity to reduce iron-mediated neurotoxicity, inhibit T-cell and B-cell proliferation, and exert antioxidative effects. nih.gov

Data from a study screening generic drugs for progressive MS: