Fluoxetine

Inhibition of Serotonin Reuptake at the Presynaptic Terminal

This compound exerts its primary effect by blocking the reuptake of serotonin (5-hydroxytryptamine or 5-HT) at the presynaptic neuron terminal. This is achieved by inhibiting the serotonin transporter (SERT) protein. nih.govnih.govpharmgkb.org By binding to the reuptake pump on the neuronal membrane, this compound prevents the transport of serotonin back into the presynaptic neuron. wikipedia.org This inhibition leads to an increased concentration of serotonin in the synaptic cleft, thereby enhancing serotonergic neurotransmission. nih.govwikipedia.orgdrugbank.com This increased availability of serotonin allows for prolonged stimulation of postsynaptic serotonin receptors. nih.govspandidos-publications.com

Effects on Serotonin Receptor Subtypes (e.g., 5-HT1A, 5-HT2A, 5-HT2C)

While this compound's main action is on the serotonin transporter, it also exhibits activity, albeit typically weaker, at certain serotonin receptor subtypes. This compound has been shown to have mild activity at the 5-HT2A and 5-HT2C receptors. nih.gov Chronic administration of this compound has been shown to selectively interact with the 5-HT1A receptor, potentially enhancing its G protein coupling capability. oncotarget.com Activation of the 5-HT1A receptor, which is located presynaptically in areas like the dorsal raphe nucleus, can influence downstream signaling pathways. nih.govoncotarget.com Furthermore, it has been suggested that this compound's interaction with the 5-HT2C receptor may contribute to increases in norepinephrine and dopamine levels in the prefrontal cortex, particularly at higher concentrations. wikipedia.orgdrugbank.com Activation of postsynaptic 5-HT1A receptors has also been linked to the regulation of GSK-3β/β-catenin signaling, a pathway implicated in neurogenesis. oup.com

Impact on Serotonin Levels in Cerebrospinal Fluid

Studies have investigated the impact of this compound on serotonin levels in the cerebrospinal fluid (CSF). Low concentrations of serotonin have been observed in the CSF of patients with depression. nih.govdrugbank.com While direct measurements of serotonin increases in CSF due to this compound are complex, the inhibition of reuptake is understood to increase extracellular serotonin levels in various brain regions, including those that influence CSF composition. drugbank.comspandidos-publications.com Research has also explored the effect of this compound on neurosteroid levels in CSF, noting that this compound treatment can normalize decreased levels of allopregnanolone in the CSF of patients with major depression, and this normalization has shown a correlation with symptom improvement. nih.govquotidianosanita.it

Neurotrophic Factor Modulation

This compound's effects extend to the modulation of neurotrophic factors, which are crucial for neuronal survival, growth, and plasticity.

Brain-Derived Neurotrophic Factor (BDNF) Signaling

Brain-Derived Neurotrophic Factor (BDNF) and its receptor, tropomyosin receptor kinase B (TrkB), are considered key players in the neuroplastic changes associated with the therapeutic effects of antidepressants, including this compound. frontiersin.orgresearchgate.netjneurosci.org Chronic administration of this compound has been widely reported to increase both BDNF mRNA and protein expression in vivo. researchgate.net Studies in primary cortical neurons have shown that this compound can induce both mRNA and protein expression of BDNF, as well as mRNA expression of immediate early genes related to the TrkB signaling pathway. researchgate.net This effect appears to involve TrkB receptor activation and, in some contexts, may be independent of the serotonin transporter. researchgate.net

BDNF binding to TrkB is typically associated with the activation of intracellular signaling pathways such as the Ras-MAPK, PI3-K, and PLCγ pathways, which are involved in processes like proliferation, differentiation, survival, and neurite extension. researchgate.net Research suggests that this compound's ability to enhance BDNF/TrkB signaling is fundamental to the activity-dependent synaptic plasticity that contributes to mood improvements. frontiersin.org Furthermore, studies indicate that this compound may directly bind to the TrkB receptor, facilitating its synaptic localization and activation by BDNF. frontiersin.org The increase in extracellular serotonin resulting from this compound's reuptake inhibition can act on receptors like 5-HT1A, which in turn can activate pathways leading to the expression of BDNF. oncotarget.com The reciprocal interaction between serotonin and BDNF may synergize the pharmacological effects of this compound. oncotarget.com this compound has also been shown to upregulate BDNF expression in astrocytes, suggesting a potential role of glial cells in its neurotrophic effects, possibly contributing to normalizing trophic and metabolic support to neurons. nih.gov Studies using BDNF heterozygous animals suggest that BDNF is crucial for this compound-induced effects. biorxiv.org

The effects of this compound on BDNF expression have been observed in various brain regions, including the hippocampus and prefrontal cortex. spandidos-publications.comjneurosci.orgbiorxiv.org Chronic this compound treatment has been shown to increase BDNF levels in the dorsal hippocampus, while acute treatment may increase levels in the ventral hippocampus, suggesting regional specificity in its effects. biorxiv.org

Below is a summary of research findings on this compound's impact on BDNF:

Tropomyosin Receptor Kinase B (TrkB) Activation

This compound has been shown to activate the tropomyosin receptor kinase B (TrkB), the primary receptor for brain-derived neurotrophic factor (BDNF). This activation is considered fundamental to the activity-dependent synaptic plasticity observed with this compound treatment. Research suggests that this compound can directly bind to the TrkB receptor, allosterically promoting its signaling frontiersin.orgmdpi.com. This direct binding facilitates the synaptic localization of TrkB and enhances its activation by BDNF frontiersin.org. Different experimental approaches support the idea that enhanced BDNF/TrkB signaling is crucial for the mood improvements associated with this compound treatment frontiersin.org. Antidepressants, including this compound, are thought to facilitate the ability of BDNF to activate TrkB receptors in parvalbumin-positive (PV) interneurons through several mechanisms, including direct binding, inhibiting dephosphorylation of TrkB, and reducing TrkB endocytosis frontiersin.org. Studies using genetically modified mice have demonstrated that the plasticity-related and antidepressant-like responses to this compound are lost in animals with a mutation in the TrkB transmembrane domain that abolishes antidepressant binding, further supporting TrkB as a direct target frontiersin.org.

Vascular Endothelial Growth Factor (VEGF) Enhancement

Studies indicate that this compound can enhance the levels of Vascular Endothelial Growth Factor (VEGF). VEGF is a trophic factor known to regulate angiogenesis and also possesses neurotrophic and neuroprotective properties in the central and peripheral nervous systems researchgate.net. Chronic this compound administration has been shown to increase endothelial cell proliferation in the subgranular zone (SGZ) of the hippocampus, and VEGF receptor signaling has been identified as a mediator of this effect researchgate.netnih.gov. Research in patients with vascular cognitive impairment has also shown that this compound treatment can increase serum concentrations of VEGF nih.govnih.govresearchgate.net. This enhancement of VEGF may contribute to the remodeling of hippocampal circuitry and increased neurogenesis and angiogenesis researchgate.net.

Neurogenesis and Synaptogenesis

This compound treatment has been extensively studied for its effects on neurogenesis (the birth of new neurons) and synaptogenesis (the formation of new synapses), particularly in the adult brain.

Stimulation of Adult Neurogenesis (Hippocampus, Dentate Gyrus)

Chronic this compound treatment is known to stimulate neurogenesis in the adult hippocampus, specifically in the dentate gyrus (DG) frontiersin.orgkyoto-u.ac.jpnih.govmdpi.compnas.orgpnas.org. This increase in the production of new neurons is considered a potential mechanism underlying the behavioral effects of this compound kyoto-u.ac.jppnas.org. This compound has been shown to facilitate various stages of neurogenesis, including progenitor proliferation, survival, and the early phase of maturation frontiersin.org. It can also counteract the decline in neurogenesis caused by chronic stress frontiersin.orgfrontiersin.org. Studies using reporter mouse lines have indicated that this compound primarily targets an early progenitor cell class in the adult DG, increasing symmetric divisions and leading to an expansion of this cell population pnas.org. While increased hippocampal neurogenesis is a notable effect, some research suggests that functional modifications of existing neurons may also be necessary for the full action of antidepressants researchgate.net.

This compound also appears to promote neurogenesis of interneurons in the cerebral cortex frontiersin.orgkyoto-u.ac.jpnih.gov. Studies in adult marmosets showed increased expression of markers for immature neurons in the hippocampal dentate gyrus and increased generation of cortical interneurons following this compound treatment kyoto-u.ac.jpnih.gov.

Effects on Neuronal Plasticity and Network Remodeling

This compound promotes various forms of plasticity in the adult central nervous system, including structural remodeling of neurons and alterations in synaptic connectivity oup.commdpi.comnih.gov. These changes in neuroplasticity are thought to strengthen synaptic connectivity and contribute to the remodeling of neuronal circuits in emotional pathways mdpi.com. Chronic this compound treatment induces adaptive changes in forebrain structures, including modifications at glutamatergic synapses frontiersin.org. The neuroplastic effects have been observed in diverse neural systems, including the visual cortex and hippocampus biorxiv.org. This compound can restore in adult animals the plastic potential characteristic of earlier stages of postnatal life, which may facilitate the functional and structural recovery of neuronal networks nih.gov.

Alterations in Dendritic Spine Density

This compound treatment has been shown to increase dendritic spine density in various brain regions, including the hippocampus and medial prefrontal cortex frontiersin.orgoup.commdpi.com. Dendritic spines are the postsynaptic sites of most excitatory synapses, and changes in their density and morphology are indicative of synaptic plasticity plos.orgnih.gov. Chronic this compound treatment can lead to the development of robust and larger spines enriched with receptor subunits associated with enhanced synaptic responses frontiersin.org. Studies have observed an increase in dendritic spine density in the hippocampus of rodents and in cortical interneurons oup.commdpi.comfrontiersin.orgplos.orgnih.gov. For instance, chronic this compound treatment in mice induced the appearance of large-sized spines in the dentate gyrus plos.org. The effect on spine density can vary depending on the brain region, age, and duration of treatment frontiersin.orgmdpi.comfrontiersin.orgnih.gov.

Table 1: Observed Effects of this compound on Dendritic Spine Density

Myelination and Gene Expression

Research suggests that this compound can influence myelination and the expression of genes related to this process. Myelination, the formation of the myelin sheath around nerve fibers, is crucial for efficient neuronal communication and contributes to brain connectivity dntb.gov.ua. Studies in rats have shown that perinatal exposure to this compound can affect myelin-related gene expression in regions like the prefrontal cortex and basolateral amygdala, with effects potentially being sex-specific nih.govbiorxiv.org. Chronic this compound exposure has also been found to cause long-term changes in the expression of genes involved in myelination in the hippocampus of adult rats dntb.gov.uaresearchgate.net. Gene ontology analysis in one study revealed that upregulated genes induced by chronic this compound exposure were significantly enriched for genes involved in myelination dntb.gov.uaresearchgate.net. Specific myelin-related genes like Transferrin (Tf) and Ciliary neurotrophic factor (Cntf) have shown altered expression following this compound exposure dntb.gov.uaresearchgate.net. These findings suggest that this compound's effects extend to influencing the structural components that support neuronal network function.

Anti-inflammatory and Neuroprotective Properties

Reduction of Neuroinflammation

Studies indicate that this compound can reduce neuroinflammation by modulating the levels of pro-inflammatory cytokines. Research in animal models of depression has shown that this compound treatment can suppress neuroinflammation in the hippocampus. frontiersin.orgnih.gov This involves reducing the activation of microglia and astrocytes and decreasing the release of pro-inflammatory cytokines such as interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). frontiersin.orgnih.govexplorationpub.comnih.gov The anti-inflammatory effects may be mediated through multiple signaling pathways, including the inhibition of the p38 mitogen-activated protein kinase (MAPK) pathway and the disruption of nuclear factor-kappa B (NF-κB) signaling. frontiersin.orgnih.govfrontiersin.org

Table 1: Effects of this compound on Pro-inflammatory Cytokine Levels in Animal Models

Inhibition of Apoptosis and Neuronal Injury

This compound exhibits anti-apoptotic properties, contributing to the preservation of neuronal integrity and function. nih.govnih.gov It has been shown to mitigate neuronal injury induced by various insults, including chronic stress and ischemia/reperfusion. frontiersin.orgnih.govmdpi.com Mechanisms involved in the anti-apoptotic effects include the reduction of apoptosis mediators and oxidative substances. nih.gov Studies have demonstrated that this compound can decrease neuronal apoptosis by inhibiting pathways such as the p38 MAPK pathway and modulating proteins like caspase-3. frontiersin.orgnih.govaging-us.comnih.gov In models of early brain injury, this compound treatment significantly attenuated apoptosis and the expression of apoptosis-related proteins. nih.gov Furthermore, this compound has been shown to protect neurons against microglia-mediated neurotoxicity, partly by inhibiting microglial activation and the subsequent release of pro-inflammatory factors. nih.gov

Table 2: Effects of this compound on Neuronal Apoptosis and Injury

Modulation of Neurosteroid Levels

This compound has been found to modulate the levels of neurosteroids in the brain, which are known to act as allosteric modulators of neurotransmitter receptors, particularly the GABAA receptor. pnas.orgfrontiersin.orggoogle.com This modulation is hypothesized to contribute to the anxiolytic effects of this compound, potentially explaining rapid effects observed before significant serotonin reuptake inhibition occurs. novapublishers.comfrontiersin.orgresearchgate.net Research indicates that this compound can increase brain levels of neurosteroids such as allopregnanolone (3α, 5α-THP). pnas.orgfrontiersin.orgresearchgate.netresearchgate.net This increase may occur through direct interference with enzymes involved in neurosteroid synthesis, such as 3α-hydroxysteroid oxidoreductase, or by inhibiting competing pathways. pnas.orgfrontiersin.orgresearchgate.net Studies in both rats and depressed patients have shown elevated levels of allopregnanolone in the brain and cerebrospinal fluid following this compound treatment. pnas.orgfrontiersin.orgresearchgate.net

Table 3: Effects of this compound on Neurosteroid Levels

Glutamatergic Neurotransmission Modulation

While primarily known for its effects on the serotonergic system, this compound also appears to modulate glutamatergic neurotransmission. frontiersin.org Glutamate is the primary excitatory neurotransmitter in the mammalian nervous system and plays a crucial role in various brain functions, including mood and cognition. nih.gov The precise mechanisms by which this compound influences glutamatergic signaling are still under investigation, but this modulation may contribute to its therapeutic effects and potentially its impact on neuroplasticity. novapublishers.com

Sigma-1 Receptor Action

This compound has been shown to interact with the sigma-1 receptor. frontiersin.org The sigma-1 receptor is a chaperone protein located at the endoplasmic reticulum that modulates various cellular processes, including calcium signaling, protein folding, and neurotransmission. Activation of this receptor has been linked to anti-inflammatory and neuroprotective effects in certain cell culture models. explorationpub.com this compound's action at the sigma-1 receptor may contribute to its effects on neuroinflammation and neuroprotection, independent of its primary action on serotonin reuptake. frontiersin.orgexplorationpub.com

Functional Inhibition of Acid Sphingomyelinase (FIASMA) and the Ceramide System

This compound is recognized as a functional inhibitor of acid sphingomyelinase (FIASMA). pnas.org Acid sphingomyelinase is an enzyme involved in the hydrolysis of sphingomyelin into ceramide. nih.govdisprot.org Modulation of this enzyme and the resulting levels of ceramide can impact various cellular processes, including apoptosis, inflammation, and cell signaling. metabolomicsworkbench.orgciteab.comnih.gov By inhibiting acid sphingomyelinase, this compound can alter the balance of sphingolipids, potentially contributing to its observed anti-apoptotic and anti-inflammatory effects. pnas.org

Table 4: Overview of this compound's Actions on the Ceramide System

Impact on mTOR Pathway

Research into the neurobiological mechanisms of this compound action has increasingly focused on intracellular signaling pathways, including the mammalian target of rapamycin (mTOR) pathway. The mTOR pathway is recognized for its critical role in various neuronal functions, such as protein synthesis, synaptic plasticity, neurogenesis, and cell survival, processes implicated in the pathophysiology and treatment of mood disorders. oup.comcsic.es

Studies have demonstrated that chronic treatment with this compound can influence mTOR signaling in a region-dependent manner in the brain. Specifically, chronic administration of this compound has been shown to attenuate the reduction in mTOR phosphorylation induced by chronic unpredictable mild stress (CUMS) in the hippocampus and amygdala of mice. researchgate.netnih.govnih.govscite.ai This suggests that this compound can counteract stress-induced impairments in mTOR pathway activity in these key brain regions associated with mood regulation. However, this effect was not consistently observed in other regions like the frontal cortex or hypothalamus in some studies. researchgate.netnih.govnih.gov

Activation of the mTOR signaling pathway by chronic this compound treatment appears to be crucial for its antidepressant-like effects and its impact on synaptic plasticity. Research indicates that this compound-induced increases in synaptic protein levels, such as PSD-95 and synapsin I, in the hippocampus are mediated through the activation of the mTOR pathway. researchgate.netnih.govnih.gov These effects on synaptic proteins, which are vital for synaptic structure and function, were blocked by co-administration of rapamycin, a known inhibitor of mTOR. researchgate.netnih.govnih.govfrontiersin.org This provides strong evidence that the mTOR pathway is a necessary component for at least some of the neurobiological effects of this compound, particularly those related to synaptic plasticity in the hippocampus. nih.govfrontiersin.org

Upstream regulators of the mTOR pathway, including the PI3K/Akt and MAPK/ERK pathways, have also been implicated in the effects of antidepressants. Some studies suggest that this compound may influence these upstream molecules, which can subsequently lead to mTOR activation. frontiersin.orgoup.com The BDNF-TrkB signaling pathway is also considered an upstream activator that can converge on mTORC1 signaling, and this compound has been shown to affect BDNF levels and TrkB signaling, potentially contributing to mTOR activation. frontiersin.orgmdpi.com

While chronic this compound treatment consistently shows an impact on mTOR signaling in specific brain regions in vivo, some in vitro studies in cultured hippocampal neurons have presented findings suggesting that while this compound increases upstream regulators like phospho-Akt and phospho-ERK, its effects on synaptic proteins might occur through mechanisms independent of direct mTOR activation in that specific context. oup.com This highlights the complexity of this compound's mechanisms and potential differences between in vitro and in vivo conditions or regional variations in signaling reliance.

Absorption and Bioavailability

This compound is well absorbed following oral administration. hres.ca Despite extensive absorption, hepatic first-pass metabolism reduces its oral bioavailability to below 90%. mdpi.comdrugbank.com Some sources indicate bioavailability between 60% and 80%. wikipedia.org Peak plasma concentrations are typically reached within 6 to 8 hours after a single oral dose. hres.camims.com Food does not appear to significantly affect the systemic bioavailability of this compound, although it may slightly delay absorption. hres.ca

Distribution and Tissue Accumulation

This compound is highly lipophilic and exhibits a large volume of distribution (Vd), ranging from 12 to 100 L/kg, which indicates substantial accumulation in tissues. mdpi.comdrugbank.compharmgkb.orgscielo.br Compared to other SSRIs, this compound has the highest volume of distribution. mdpi.com It is highly bound to plasma proteins, primarily albumin and α₁-acid glycoprotein, with approximately 94-95% protein binding. drugbank.comwikipedia.orgmims.com This high protein binding allows the drug and its active metabolite, northis compound, to distribute to the brain. drugbank.com this compound is widely distributed throughout the body and readily crosses the blood-brain barrier. mims.com While it accumulates in several tissues, its accumulation in the brain is reported to be significantly lower compared to some other SSRIs, with a brain to plasma ratio of 2.6:1 in patients. mdpi.compharmgkb.org Tissue distribution studies in animals have shown this compound to be most highly concentrated in the lungs, with distribution coefficients relative to whole blood being significantly higher in the lungs (60x), liver (38x), spleen (20x), brain (15x), heart (10x), and kidneys (9x). nih.gov

Metabolism and Metabolites

This compound undergoes extensive metabolism in the liver, primarily through the cytochrome P450 enzyme system. pharmgkb.orgresearchgate.netfda.gov

The primary metabolic pathway for this compound is N-demethylation, which produces the only identified active metabolite, northis compound. hres.capharmgkb.orgresearchgate.netfda.gov Northis compound is also an SSRI and contributes to the long duration of action of this compound. hres.caresearchgate.net this compound is administered as a racemic mixture of two enantiomers, R- and S-fluoxetine. pharmgkb.org S-fluoxetine is slightly more potent in inhibiting serotonin reuptake than R-fluoxetine. pharmgkb.orgmedcraveonline.com This difference in potency is more pronounced for the active metabolite, with S-northis compound having approximately 20 times greater reuptake blocking potency than R-northis compound. pharmgkb.orgmedcraveonline.com The formation of northis compound from this compound is stereoselective. researchgate.net

Multiple cytochrome P450 (CYP) enzymes are involved in the metabolism of this compound to its N-desmethyl metabolites, including CYP2D6, CYP2C19, CYP2C9, CYP3A4, and CYP3A5. mdpi.compharmgkb.orgmedcraveonline.comnih.gov While several enzymes contribute to the N-demethylation of this compound, CYP2D6, CYP2C9, and CYP3A4 appear to be the major contributing enzymes for phase I metabolism. drugbank.com In vivo studies in humans indicate that CYP2D6 plays a significant role. researchgate.net However, this compound and northis compound are inhibitors of CYP2D6-mediated reactions. mdpi.compharmgkb.orgmedcraveonline.com Consequently, the involvement of CYP2C19, CYP2C9, CYP3A4, and CYP3A5 in this compound metabolism becomes more prominent during chronic administration as CYP2D6 activity is reduced due to this inhibition. mdpi.compharmgkb.org In vitro studies have also shown this compound to have inhibitory efficacy against CYP2C19, CYP2C9, and CYP3A4. mdpi.compharmgkb.orgmedcraveonline.com In addition to N-demethylation, this compound and potentially northis compound undergo O-dealkylation mediated by CYP2C19 and CYP3A4, producing para-trifluoromethylphenol, which is subsequently metabolized to hippuric acid. drugbank.comnih.gov

The cytochrome P450 isoforms, particularly CYP2D6, exhibit genetic variations that impact their catalytic activity. mdpi.compharmgkb.org CYP2D6 is a highly polymorphic enzyme, and genetic variability in its function can be clinically important regarding this compound metabolism. wikipedia.orgnih.gov Studies have demonstrated that individuals with genetically predicted CYP2D6 poor metabolizer status (having two no-function alleles) tend to have higher steady-state plasma concentrations of this compound and lower concentrations of northis compound. researchgate.net This genetic polymorphism contributes to the interindividual variability observed in this compound plasma concentrations. nih.govresearchgate.net The frequency of CYP2D6 poor metabolizers varies among ethnic groups, being approximately 5-10% in Caucasians and 1% in East Asians. bpac.org.nz

Table 1: Key Pharmacokinetic Parameters of this compound

Table 2: Cytochrome P450 Enzymes Involved in this compound Metabolism

Self-Inhibition of Metabolism

This compound and its active metabolite, northis compound, are known inhibitors of certain cytochrome P450 (CYP) enzymes, particularly CYP2D6. wikipedia.orgnih.govmedcraveonline.com This inhibitory activity can lead to the self-inhibition of their own metabolism. wikipedia.orguzh.ch As a result, the elimination half-life of this compound can increase with chronic use compared to a single dose. wikipedia.org This self-inhibition contributes to the non-linear pharmacokinetics observed at higher doses. mdpi.comnih.gov While CYP2D6 is a major enzyme involved in the metabolism of this compound to northis compound, other enzymes such as CYP2C9, CYP2C19, CYP3A4, and CYP3A5 also play a role, and their influence may become more significant during chronic administration when CYP2D6 activity is diminished due to inhibition by this compound and northis compound. medcraveonline.comdrugbank.compharmgkb.org

Elimination and Half-Lives

This compound is extensively metabolized in the liver, primarily through oxidative metabolism and conjugation. pharmgkb.orgpharmgkb.org The main metabolic pathway involves the N-demethylation of this compound to its active metabolite, northis compound. nih.govpharmgkb.org Approximately 2.5% of the administered dose is excreted unchanged in the urine. nih.gov Both this compound and northis compound have long elimination half-lives, which is a distinguishing feature compared to other antidepressants. wikipedia.org The elimination half-life of this compound typically ranges from 1 to 3 days after acute administration and increases to 4 to 6 days after chronic use. wikipedia.orgdrugbank.comnih.gov The half-life of northis compound is even longer, ranging from 4 to 16 days after both acute and chronic administration. uzh.chdrugbank.commedicines.org.uk These long half-lives contribute to the significant accumulation of this compound and northis compound in the body during chronic treatment and result in a prolonged presence of the drug for several weeks after discontinuation. drugbank.commedicines.org.uknih.gov

Non-linear Pharmacokinetics at Higher Doses

The pharmacokinetics of this compound exhibit non-linear characteristics, particularly at higher doses. mdpi.comnih.govnih.gov This is indicated by a disproportionate increase in plasma levels as the dosage is increased. uzh.chmdpi.comnih.gov This non-linearity is attributed, in part, to the self-inhibition of metabolism by this compound and northis compound, primarily affecting CYP2D6. wikipedia.orguzh.ch As enzyme activity becomes saturated or inhibited at higher drug concentrations, the rate of metabolism does not increase proportionally with the dose, leading to higher-than-predicted plasma concentrations. mdpi.comfda.gov This characteristic is important to consider when adjusting doses, as it can lead to significant increases in drug exposure. uzh.chmdpi.com

Selectivity for Serotonin Transporter (SERT/SLC6A4)

This compound is classified as a selective serotonin reuptake inhibitor (SSRI). wikipedia.orgnih.gov Its primary mechanism of action involves the potent inhibition of the serotonin transporter (SERT), also known as SLC6A4. pharmgkb.orgnih.govnih.govpsychopharmacologyinstitute.combiologists.com SERT is responsible for the reuptake of serotonin from the synaptic cleft back into the presynaptic neuron, a process that terminates the action of serotonin. biologists.comwikipedia.org By blocking SERT, this compound increases the concentration and prolongs the presence of serotonin in the synaptic space, thereby enhancing serotonergic neurotransmission. wikipedia.orgnih.govnih.gov This selective inhibition of serotonin reuptake is considered the main contributor to its antidepressant effects. nih.govnih.gov

Minimal Activity on Noradrenergic and Dopaminergic Reuptake (at therapeutic doses)

At therapeutic doses, this compound exhibits minimal or no appreciable inhibitory activity on the reuptake of norepinephrine and dopamine. wikipedia.orgnih.govnih.govmedcentral.com This selectivity for the serotonin transporter distinguishes it from tricyclic antidepressants and serotonin-norepinephrine reuptake inhibitors (SNRIs), which inhibit the reuptake of both serotonin and norepinephrine. medscape.org While this compound is primarily a SERT inhibitor, some research suggests that at higher concentrations, it may interact with other systems, such as acting as an antagonist at 5HT2C receptors, which could indirectly influence norepinephrine and dopamine levels in certain brain regions like the prefrontal cortex. wikipedia.orgpsychopharmacologyinstitute.com However, its direct effect on noradrenergic and dopaminergic reuptake at typical therapeutic doses is considered negligible. wikipedia.orgnih.govnih.govmedcentral.com

Efficacy in Adult and Pediatric Populations

In adult populations, meta-analyses of clinical trials have indicated that this compound is more effective than placebo in the treatment of MDD. wikipedia.orgpharmaceutical-journal.com Studies have shown significant improvement in depressive symptoms in adults treated with this compound. dovepress.com

The efficacy of this compound in children and adolescents with MDD has been established in placebo-controlled clinical trials. fda.govnih.gov Studies involving pediatric outpatients diagnosed with MDD have shown that this compound produced a statistically significantly greater mean change from baseline compared to placebo on measures of depression severity, such as the Children's Depression Rating Scale-Revised (CDRS-R). fda.govnih.govopenrepository.com For instance, a meta-analysis of randomized controlled trials in children and adolescents with MDD found a mean change from baseline in CDRS-R favoring this compound treatment. nih.govopenrepository.com The efficacy of this compound for MDD has been demonstrated in pediatric outpatients aged 8 to 18 years. fda.gov

Comparison with Placebo and Other Antidepressants

Clinical trials have consistently shown this compound to be more effective than placebo in treating MDD in adults. wikipedia.orgpharmaceutical-journal.comnih.gov A large meta-analysis of 522 double-blind, randomized controlled trials found that all 21 antidepressants included, including this compound, were more efficacious than placebo for the acute treatment of adults with MDD. pharmaceutical-journal.comox.ac.uk

When compared to other antidepressants, particularly older tricyclic antidepressants (TCAs), this compound has shown comparable efficacy in treating depressive symptoms. nih.govnih.gov Some studies have found no statistically significant difference in efficacy between this compound and TCAs as a class. nih.gov However, some meta-analyses suggest that while all antidepressants are more effective than placebo, there are differences in efficacy among them, with some, like escitalopram and sertraline, showing higher response rates than others, including this compound, in adults. pharmaceutical-journal.comox.ac.uk Conversely, this compound has been found to be more tolerable than TCAs, leading to potentially better patient compliance. nih.govnih.gov

In pediatric populations, while this compound has demonstrated efficacy over placebo, a meta-analysis suggested that the effect size in children and adolescents is smaller than that observed in adults. mrctcenter.org This analysis indicated that the largest reduction in CDRS-R score compared to placebo was seen with sertraline, followed by this compound. mrctcenter.org

Rapid Onset of Antidepressant Effect

While the full therapeutic effects of this compound typically become evident over several weeks, some studies suggest that early improvements in depression symptoms may occur sooner. consensus.app Analyses of clinical trial data have indicated statistically significant improvement in depression symptoms with this compound compared to placebo as early as the first week of treatment. nih.govconsensus.appnih.gov However, the probability of achieving a full clinical response may not differ significantly from placebo in the very initial phase. consensus.app Continued improvement is generally observed over a longer period. consensus.app

Role in Treatment-Resistant Depression (in combination with Olanzapine)

For patients with treatment-resistant depression (TRD), defined generally as a failure to respond to at least two antidepressant trials, the combination of this compound and the atypical antipsychotic olanzapine has shown superior efficacy compared to monotherapy with either agent. dovepress.compsychiatryonline.orgresearchgate.netresearchgate.netmedigraphic.com This combination is an FDA-approved medication for bipolar depression, including cases of TRD. nih.gov

Studies have shown that the olanzapine/fluoxetine combination can lead to greater improvement in depressive symptoms and higher response and remission rates compared to this compound alone in patients with TRD. dovepress.comresearchgate.netmedigraphic.com The improvement with the combination therapy can also occur earlier than with this compound monotherapy. researchgate.netresearchgate.net Clinical trials have demonstrated rapid reduction in depression rating scale scores with the olanzapine/fluoxetine combination in patients who had responded inadequately to antidepressant monotherapy. dovepress.com

Efficacy in Adult and Pediatric Populations

The efficacy of this compound for the treatment of obsessions and compulsions in adult patients with OCD has been established in clinical trials. fda.gov Studies have shown significant reduction in OCD symptom severity with this compound treatment. fda.gov

This compound is also effective for treating OCD in children and adolescents. wikipedia.org Its efficacy in this population has been demonstrated in placebo-controlled clinical trials. fda.govnih.govkglmeridian.com Studies in pediatric patients with OCD have shown that this compound is associated with significantly greater reduction of OCD symptom severity compared with placebo, as measured by scales such as the Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS). fda.govnih.govkglmeridian.com Meta-analyses of SSRIs in the treatment of childhood and adolescent OCD have indicated that this compound is more effective than placebo. psychiatryonline.org

Here is a summary of some key efficacy findings:

Post-Traumatic Stress Disorder (PTSD)

A meta-analysis of randomized controlled trials concluded that this compound could be an effective treatment for PTSD, showing higher responder status and less severe PTSD symptoms at trial endpoint compared to placebo groups. nih.govnsj.org.sa Another double-blind, randomized, placebo-controlled study conducted in various regions found that this compound was associated with greater improvement from baseline in PTSD symptom scores than placebo, with statistically significant differences observed relatively early in treatment. psychiatrist.compsychiatrist.com Compared with placebo, this compound was also associated with significantly greater improvement in total symptom scores and intrusive and hyperarousal subscores, as well as improvements in measures of global impression, anxiety, and depression. psychiatrist.compsychiatrist.com

Generalized Anxiety Disorder (GAD)

While widely used in clinical practice for Generalized Anxiety Disorder (GAD), the evidence supporting this compound's efficacy specifically for GAD in some populations has been considered limited. nih.govnih.govresearchgate.net Reviews of clinical trials, particularly in Chinese patients, have noted that while short-term efficacy had been established in open-label, head-to-head controlled trials comparing this compound to other anxiolytics, there was a lack of strong evidence from placebo-controlled studies. nih.govnih.govresearchgate.net These reviews often highlight the high risk of bias in the included studies, small sample sizes, and the absence of placebo control groups as limitations. nih.govnih.govresearchgate.net

Some research suggests that this compound may have a rapid onset of action in GAD, potentially within 1-2 weeks, and may be effective in maintenance treatment. nih.govnih.govresearchgate.net However, definitive recommendations for this compound as a reliable first-line treatment for GAD, particularly in certain populations, have been cautious due to the limitations in the available research. nih.govnih.govresearchgate.net

Impulsive Aggression

This compound has been investigated for its potential to reduce impulsive aggressive behavior. nih.govjwatch.orgresearchgate.netfrontiersin.orgfrontiersin.org Central serotonergic system dysfunction is thought to be related to impulsive aggressive behavior, and pharmacologic enhancement of serotonin activity could potentially reduce this behavior. nih.govresearchgate.netfrontiersin.org

A double-blind, randomized, placebo-controlled trial in individuals with Intermittent Explosive Disorder (IED) and histories of impulsive aggressive behavior found that this compound treatment resulted in a sustained reduction in aggression and irritability scores. nih.govresearchgate.net This reduction was apparent relatively early in the treatment course. nih.govresearchgate.net this compound was also found to be superior to placebo in the proportion of responders based on global improvement scales. nih.govresearchgate.net Closer examination of the data revealed that a percentage of this compound-treated subjects achieved full or partial remission of impulsive aggressive behaviors. nih.govresearchgate.net

Another study evaluating the anti-aggressive efficacy of this compound in patients with personality disorders and a history of impulsive aggression demonstrated that this compound led to a significant reduction in scores for verbal aggression, aggression against objects, and irritability compared with placebo. jwatch.org These findings suggest that SSRIs like this compound can diminish impulsive aggression independently of their antidepressant action. jwatch.org While effective, research indicates that this compound may lead to full or partial remission of impulsive aggressive behaviors in a notable percentage of individuals with IED, but not all. nih.govresearchgate.net

Social Anxiety Disorder (limited efficacy)

Research into the efficacy of this compound for Social Anxiety Disorder (SAD), also known as social phobia, has yielded varied results. Some studies suggest that this compound may be effective in treating SAD, with observed improvements in measures of social anxiety and phobic avoidance. nih.gov For instance, a 12-week open clinical trial involving 16 patients with a primary diagnosis of social phobia reported significant improvement in symptoms from baseline to endpoint in the majority of patients who completed the trial. nih.gov Another study in children and adolescents aged 7 to 17 with SAD indicated that this compound was significantly effective and well tolerated, with the beneficial effect increasing over time. psychiatry-psychopharmacology.compsikofarmakoloji.org Factors such as younger age, lower baseline social anxiety scores, absence of a family history of depression and/or anxiety disorders, and lower maternal social anxiety scores were suggested to predict a better outcome in this population. psychiatry-psychopharmacology.compsikofarmakoloji.org

However, other studies have presented less conclusive findings. Two placebo-controlled trials of this compound for SAD have reported negative results. psychiatrist.com While a large two-site trial found efficacy for both this compound and cognitive-behavioral therapy (CBT) over placebo in patients with generalized social phobia, the response rates for this compound alone were comparable to those for CBT alone or CBT plus placebo. psychiatrist.com

Cataplexy

This compound has a role in the treatment of cataplexy, a symptom often associated with narcolepsy. jtsm.org It is noted for its effectiveness in reducing cataplexy attacks. jtsm.org While systematic research evidence specifically supporting antidepressants for cataplexy may be limited, this compound, as a selective serotonin reuptake inhibitor (SSRI), is frequently used in the treatment of cataplexy in narcolepsy. bioprojet.nldovepress.com Limited data from Class III and Class IV evidence studies have reported minor improvements in cataplexy with this compound. bioprojet.nl A pilot study evaluating this compound in six patients with poorly controlled cataplexy showed a mean reduction of 92% in the number of cataplectic episodes per week after 20 weeks of treatment. nih.govneurology.org

Alcohol Dependence

The efficacy of this compound in treating alcohol dependence, particularly in patients with comorbid depression, has been investigated. A 12-week double-blind, placebo-controlled trial involving patients with comorbid major depressive disorder and alcohol dependence demonstrated that the this compound group showed significantly greater improvement in depressive symptoms and lower total alcohol consumption compared to the placebo group. nih.gov A 1-year follow-up study of patients from a previous 3-month trial also indicated that the this compound group continued to show less depression and less drinking than the placebo group. researchgate.net

However, the results are not consistently positive across all studies. A placebo-controlled, double-blind study of this compound in male patients with severe alcohol dependence without other Axis I disorders did not find a reduction in clinically significant relapse rates. nih.gov In this study, supportive living arrangements after hospital discharge were associated with reduced relapse rates, rather than this compound treatment. nih.gov Another placebo-controlled trial in alcohol-dependent subjects without comorbid major depression found no significant effects of this compound on alcohol consumption, although it did reduce depression scores in subjects with current major depression. psychiatryonline.org

Trichotillomania

Studies investigating the efficacy of this compound for trichotillomania (hair pulling disorder) have largely shown limited benefit. Several studies have reported no significant changes in hair-pulling severity compared to waitlist or placebo groups. mdpi.com For example, a long-term, double-blind, placebo-controlled crossover trial involving adult chronic hair pullers found no significant differences between this compound and placebo treatments across various measures of hair pulling and urge to pull. nih.gov Similarly, an 18-week placebo-controlled, double-blind crossover study did not demonstrate the short-term efficacy of this compound in treating trichotillomania. psychiatryonline.org

In comparative studies, behavioral therapy, such as habit reversal, has demonstrated superiority over this compound in reducing trichotillomania symptoms. jwatch.orgnih.gov A 12-week randomized, waiting-list controlled study comparing behavioral therapy and this compound found that the behavioral therapy group showed a significantly greater reduction in symptoms and higher effect sizes than the this compound and waiting-list groups. nih.gov

Selective Mutism

This compound has shown promise in the treatment of selective mutism, particularly in children and adolescents. An 8-week open-label clinical study involving 17 children with selective mutism reported that a significant majority (76%) showed improvement in measures of mutism, depression, and anxiety. jkacap.org A 9-week open trial with 21 children also found that 76% improved, exhibiting diminished anxiety and increased speech in public settings. nih.gov Improvement in this study was inversely correlated with age. nih.gov

A double-blind, placebo-controlled study involving 15 children with elective mutism (selective mutism) who did not respond to a placebo run-in period indicated that subjects treated with this compound were significantly more improved than placebo-treated subjects on parents' ratings of mutism and global change. nih.gov However, clinician and teacher ratings did not show significant differences between the treatment groups, and most subjects in both groups remained symptomatic at the end of the study. nih.gov While evidence for SSRIs in selective mutism is considered limited, this compound has the most empirical evidence among SSRIs for this condition. jpn.ca

Borderline Personality Disorder

The efficacy of this compound in the treatment of Borderline Personality Disorder (BPD) has been explored, particularly in addressing symptoms such as dysphoria and impulsive aggression. Some investigators hypothesized that this compound's antidepressant properties and serotonin reuptake inhibition could help treat BPD symptoms and potentially reduce impulsivity. the-hospitalist.org Case series and a double-blind, placebo-controlled trial have demonstrated this compound's efficacy in BPD, with one study finding its greatest impact on "anger". the-hospitalist.org

However, other research suggests that while this compound treatment can lead to a substantial reduction in impulsive aggression and severity of depression in women with BPD, other treatments, such as olanzapine monotherapy or the olanzapine-fluoxetine combination, may be associated with a significantly greater rate of improvement over time on measures of depression and impulsive aggression. nih.govpsychiatrist.com A study examining the effect of adding this compound to dialectical behavior therapy (DBT) for BPD found no significant additional benefits from this compound compared to placebo when added to this psychosocial treatment. psychiatrist.comresearchgate.net

Raynaud Phenomenon

The use of this compound in treating Raynaud Phenomenon, a condition characterized by reduced blood flow to the fingers and toes, has been debated, with limited evidence supporting its routine use. droracle.ainih.gov While some small studies suggest that SSRIs like this compound may help reduce the frequency and severity of Raynaud's attacks, the evidence is considered insufficient for routine use. droracle.ai Studies typically used higher doses than a low dose of 10 mg daily, which is not a recommended treatment due to limited evidence and potential for suboptimal dosing. droracle.ai

A 6-week crossover study comparing this compound with nifedipine in patients with primary or secondary Raynaud's phenomenon showed a reduction in attack frequency and severity with both treatments, but the effect was statistically significant only in the this compound-treated group. researchgate.netccjm.org Subgroup analysis in this study indicated that the greatest response to this compound was seen in females and in patients with primary Raynaud's phenomenon. researchgate.net However, a 2016 review found limited evidence for the efficacy of this compound in treating the condition. droracle.ai Despite some positive findings, there is insufficient scientific evidence to recommend this compound as a treatment in Raynaud's phenomenon secondary to systemic sclerosis. nih.gov

Autism Spectrum Disorder (tentative evidence in adults)

Research into the efficacy of this compound for treating core symptoms of Autism Spectrum Disorder (ASD), particularly repetitive behaviors, has yielded inconsistent results, with some studies showing promise primarily in adults. While studies in children with ASD have generally not shown a significant effect of this compound on repetitive behaviors, a double-blind placebo-controlled trial in adults with ASD reported improvements. thetransmitter.orgpsychiatryonline.orgmdpi.com

However, it is important to note that the evidence in adults is considered limited but promising, and further research is needed. psychiatryonline.orgmdpi.com

Premature Ejaculation

This compound has been investigated for its efficacy in treating premature ejaculation (PE). Studies have indicated that this compound can delay the onset of ejaculation in men with PE.

A double-blind placebo-controlled study involving 17 patients with premature ejaculation demonstrated that the intravaginal ejaculation latent period was significantly longer in the group receiving this compound compared to the placebo group. nih.gov Other studies comparing this compound to other SSRIs like citalopram and sertraline have also shown that this compound is effective in increasing intravaginal ejaculation latency time, although some studies suggest other SSRIs may have a greater effect. tandfonline.comauajournals.orgbrieflands.com A study comparing this compound and citalopram found a significant increase in ejaculation time with both drugs compared to placebo, with no significant difference in effectiveness between this compound and citalopram. Another study comparing this compound, sertraline, and clomipramine found that while all three medications and placebo increased intravaginal ejaculation latency, clomipramine was the most efficacious, followed by sertraline and then this compound. auajournals.org

COVID-19 (potential therapeutic role)

Research has explored the potential therapeutic role of this compound in the context of COVID-19, particularly regarding its potential to mitigate severe outcomes. clinicaltrials.eufrontiersin.org

Studies suggest that this compound may reduce the risk of intubation or death in patients with COVID-19, potentially through mechanisms beyond its primary serotonergic activity. frontiersin.org this compound has been found to block the production of Interleukin-6 (IL-6), a pro-inflammatory cytokine involved in the cytokine storm associated with severe COVID-19. clinicaltrials.eufrontiersin.org It may also interfere with platelet activation and aggregation by limiting serotonin uptake, potentially reducing inflammation. mdpi.com Observational studies have correlated antidepressant therapy, including this compound, with a decreased risk of intubation or death in hospitalized COVID-19 patients. frontiersin.orgucv.ve One observational cohort study showed that COVID-19 patients treated with an average dose of 20 mg of this compound had a lower risk of intubation and death. frontiersin.org

Cancer Therapy Repurposing

This compound is being investigated for its potential to be repurposed for cancer therapy, exhibiting potential oncolytic effects through various mechanisms. nih.gov

Studies suggest that this compound may have activity against several types of tumors, including brain tumors (glioblastoma), breast, liver, colon, and cervical cancers. nih.govwilliamscancerinstitute.com Its ability to cross the blood-brain barrier makes it potentially useful for treating brain tumors like glioblastoma. nih.govwilliamscancerinstitute.com In laboratory models, combining this compound with temozolomide, a standard glioblastoma chemotherapy, has shown synergistic effects, leading to increased cancer cell death and tumor regression in mice. williamscancerinstitute.combraintumor.org this compound may target tumor metabolism, inhibit signaling pathways like epidermal growth factor receptor (EGFR), induce endoplasmic reticulum stress, and activate apoptotic proteins. williamscancerinstitute.combraintumor.org It has also shown potential in overcoming drug resistance in breast cancer models and increasing sensitivity to chemotherapy agents like cisplatin in cervical cancer. nih.govwilliamscancerinstitute.com Preclinical studies also suggest this compound's potential as a novel treatment for neuroendocrine prostate cancer by inhibiting cell viability and neuroendocrine differentiation through targeting the AKT pathway. frontiersin.org

Cognitive Function Enhancement in Specific Pathologies

The impact of this compound on cognitive function is complex and appears to vary depending on the presence of underlying pathologies. While some studies suggest potential for cognitive enhancement in specific conditions, the effects are not universally observed and may be influenced by factors such as the specific pathology, dosage, and duration of treatment. frontiersin.org