Dopamine receptor; Histamine receptor; Adrenergic Receptor

Quetiapine is a novel dibenzothiazepine atypical antipsychotic. Quetiapine shows affinity for various neurotransmitter receptors including serotonin, dopamine, histamine, and adrenergic receptors and has binding characteristics at the dopamine-2 receptor similar to those of clozapine.[1]

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In vitro activity: Quetiapine exhibits binding characteristics at the dopamine-2 receptor that are similar to those of clozapine and shows affinity for a variety of neurotransmitter receptors, including adrenergic, histamine, serotonin, and dopamine receptors.[1]

Quetiapine possesses a preclinical profile that points to antipsychotic action, along with a prolonged rise in prolactin and a decreased propensity to induce extrapyramidal symptoms (EPS). In the limbic but not the motor brain regions, guetiapine modifies the expression of c-fos and neurotensin neurotransmission. In several behavioral and biochemical tests, quetiapine also exhibits clozapine-like activity and may have neuroprotective qualities.[1] Chronic restraint stress (CRS) in rats causes hippocampal cell proliferation and BDNF expression, which quetiapine dose-dependently prevents from leading to schizophrenia and depression. In stressed rats, a combination of gentapine (5 mg/kg) and Venlafaxine (2.5 mg/kg) prevents the decrease of BDNF and increases the proliferation of hippocampal cells, while individual drugs have negligible or no effects.[2] Guetiapine selectively affects the brain's limbic and cortical regions, especially the dopaminergic neurotransmission in these areas. Putamenal DA D2r occupancy is induced by gentiapine at lower levels than those observed in typical APDs. Quetiapine does not spare occupancy of the substantia nigra DA D2r, but it does produce preferential occupancy of temporal cortical DA D2r, 46.9%. In rats exposed to chronic stress through restraint, guetiapine reduces the decline in brain-derived neurotrophic factor (BDNF) in the hippocampus. Guetiapine (10 mg/kg) reverses the suppression of hippocampus neurogenesis caused by stress, as shown by an increase in pCREB-positive and BrdU-labeled cells compared to non-stressed rats, but not as much as those treated with a vehicle.[3]

In vitro binding studies [Br J Pharmacol. 2016 Jan;173(1):155-66.]
Binding assays were performed using membranes prepared by standard methods from cells stably expressing cloned human targets. Displacement binding was performed using either scintillation proximity assay (SPA) (NET/HEK293F cells and 5‐HT2C/CHO‐K1 cells) or filtration (5‐HT transporter [SERT]/HEK293 cells, dopamine transporter [DAT]/CHO‐S cells, D2S/CHO‐K1 cells, 5‐HT1A/CHO cells and 5‐HT2A/CHO cells) using tritiated radioligands (MeNER, mesulergine, MADAM [2‐(2‐dimethylaminomethyl‐phenylsulphanyl)‐5‐methyl‐phenylamine], WIN 35428, raclopride, WAY100635 and MDL100907 respectively). The majority of IC50 values were calculated with fitting model 205 in XLfit. 5‐HT2A and 5‐HT2C IC50 values were calculated using prism software by GraphPad. Mean apparent inhibition constant (K i) values were calculated using the Cheng–Prusoff equation from data derived from at least three independent experiments. In vitro assessment of affinity at glutamate receptors was performed on preparations of rat cerebral cortex tissue. Binding at NMDA receptors was evaluated with [3H]‐CGP39653 [3H]‐TCP and [3H]‐MDL 105,519 binding at kainite receptors was evaluated with [3H]‐kainic acid and binding at AMPA receptors was evaluated with [3H]‐AMPA according to standard validated protocols under conditions defined by the contractor. Compounds were evaluated in singlicate across eight concentrations (0.01, 0.1, 0.3, 1, 3, 10, 30 and 100 μM).

Cell Line: N9 microglial cells
Concentration: 0, 0.1, 1, 10, 50, and 100 μM
Incubation Time: 24 hours
Result: Had no significant effect on cell viabilities at various concentrations under 100 μM, in which significant toxicity could be observed.

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In vitro functional studies [Br J Pharmacol. 2016 Jan;173(1):155-66.]
Uptake inhibition assays were performed using HEK293F cells stably expressing human NET, SERT and DAT. Cryopreserved cells were re‐suspended at 60K per well, centrifuged at 110 g for 1 min and incubated at 37°C for 3 h. Uptake inhibition was measured using the neurotransmitter transporter dye by a method slightly modified from that reported by Jorgensen et al. 2008. The most significant alteration to the method is that fluorescence intensity was evaluated on an Envision reader. Data were analysed by calculating the % effect with respect to total (0.5% DMSO final) and background signals. D2S pA2 was measured by the ability of a compound to inhibit the response to 3 μM dopamine (~EC80), using a GTPγS filtration binding assay similar to the method previously described by Lazareno (1999; Hudzik et al., 2008). 5‐HT1A agonist activity (potency and maximal concentration [Emax]) was determined with a GTPγS SPA binding assay using membranes derived from CHO cells stably expressing recombinant human 5‐HT1A receptors. Assay conditions are based on those previously reported (Jerning et al., 2002), though modified to an SPA format. An efficacy of 100% was defined as the maximal response to 5‐HT. 5‐HT2A and 5‐HT2C antagonist activity was measured with a FLIPR‐based method, as previously reported (Porter et al., 1999) using cell lines expressing 5‐HT2A and 5‐HT2C receptors.

In animal models, the drug has a preclinical profile suggestive of antipsychotic activity with a reduced tendency to cause extrapyramidal symptoms (EPS) and sustained prolactin elevation. For example, quetiapine alters neurotensin neurotransmission and c-fos expression in limbic but not motor brain regions. The drug also demonstrates clozapine-like activity in a range of behavioral and biochemical tests and may possess neuroprotective properties. In humans, quetiapine exhibits linear pharmacokinetics with a mean terminal half-life of 7 hours. The primary route of elimination of quetiapine is through hepatic metabolism. Although not affected by smoking, alterations in quetiapine disposition due to age or hepatic impairment are manageable by appropriate dosage reduction. The optimal dosing range for quetiapine is 150 to 750 mg/day, and recent results suggest that once-daily dosing may be suitable for some patients. Finally, imaging studies with positron emission tomography confirm significant differences between quetiapine and typical antipsychotics that may be indicative of their differences in mechanism of action and propensity for producing EPS.[1]

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Animal studies demonstrate that some antipsychotics and antidepressants increase neurogenesis and BDNF expression in the hippocampus, which is reduced in volume in patients with depression or schizophrenia. We hypothesized that the better therapeutic effects of combined treatment seen in schizophrenia and depression patients are related to the additive or synergistic effects of combined treatment on hippocampal neurogenesis and BDNF expression. To test this hypothesis, we investigated the effects of chronic administration of quetiapine, venlafaxine, and their combination, on hippocampal cell proliferation and BDNF expression in rats, when subjected to chronic restraint stress (CRS) during the last 2 weeks of a 3-week drug administration period. We found (1) CRS decreased hippocampal cell proliferation and BDNF expression; (2) chronic administration of quetiapine or venlafaxine dose-dependently prevented these decreases in hippocampal cell proliferation and BDNF expression caused by CRS (6 h/day for 14 days); (3) the combination of lower doses of quetiapine (5 mg/kg) and venlafaxine (2.5 mg/kg) increased hippocampal cell proliferation and prevented BDNF decrease in stressed rats, whereas each of the drugs exerted mild or no effects; (4) individual higher doses of quetiapine (10 mg/kg) or venlafaxine (5 mg/kg) exerted effects comparable to those produced by their combination. These results support our hypothesis and can lead to future studies to develop new therapeutic approaches for treatment-resistant depression and the negative symptoms of schizophrenia.[2]

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Quetiapine is an atypical antipsychotic effective in treating the positive, negative, and cognitive symptoms of patients with schizophrenia. Our previous study has shown that chronic administration of quetiapine attenuates the decrease in levels of brain-derived neurotrophic factor (BDNF) in the hippocampi of rats subjected to chronic-restraint stress. In the present study, we investigated the effects of quetiapine on hippocampal neurogenesis that had been compromised in stressed rats. Newborn cells in the hippocampus were labeled by bromodeoxyuridine (BrdU), and immature neurons were detected immunohistochemically using an antibody against phosphorylated cAMP response element-binding protein (pCREB). The restrained rats (4 h/day for 7 days) showed lower levels of hippocampal neurogenesis indicated by decreased numbers of BrdU-labeled and pCREB-positive cells. Post-stress administration of quetiapine (10 mg/kg) for 7 or 21 days reversed the stress-induced suppression of hippocampal neurogenesis, evidenced in the numbers of BrdU-labeled and pCREB-positive cells that are comparable to those in non-stressed rats but higher than those in the vehicle-treated rats. The results may help us understand the therapeutic effects of quetiapine on cognitive deficits in patients with schizophrenia and depression, in which the structure and functions of the hippocampus are implicated.[3]

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5, 10 mg/kg

Rats

Absorption, Distribution and Excretion
Quetiapine is rapidly and well absorbed after administration of an oral dose. Steady-state is achieved within 48 hours Peak plasma concentrations are achieved within 1.5 hours. The bioavailability of a tablet is 100%. The steady-state Cmax of quetiapine in Han Chinese patients with schizophrenia after a 300 mg oral dose of the extended released formulation was approximately 467 ng/mL and the AUC at steady-state was 5094 ng·h/mL. Absorption of quetiapine is affected by food, with Cmax increased by 25% and AUC increased by 15%.
After an oral dose of radiolabeled quetiapine, less than 1% of unchanged drug was detected in the urine, suggesting that quetiapine is heavily metabolized. About 73% of a dose was detected in the urine, and about 20% in the feces.
Quetiapine distributes throughout body tissues. The apparent volume of distribution of this drug is about 10±4 L/kg.
The clearance of quetiapine healthy volunteers in the fasted state during a clinical study was 101.04±39.11 L/h. Elderly patients may require lower doses of quetiapine, as clearance in these patients may be reduced by up to 50%. Those with liver dysfunction may also require lower doses.
Quetiapine fumarate is rapidly absorbed after oral administration, reaching peak plasma concentrations in 1.5 hours. The tablet formulation is 100% bioavailable relative to solution. The bioavailability of quetiapine is marginally affected by administration with food, with Cmax and AUC values increased by 25% and 15%, respectively.
Steady state concentrations are expected to be achieved within two days of dosing.
Quetiapine is widely distributed throughout the body with an apparent volume of distribution of 10 +/-4 L/kg. It is 83% bound to plasma proteins at therapeutic concentrations.
Hepatically impaired patients (n=8) had a 30% lower mean oral clearance of quetiapine than normal subjects. In two of the 8 hepatically impaired patients, AUC and C max were 3-times higher than those observed typically in healthy subjects. Since quetiapine is extensively metabolized by the liver, higher plasma levels are expected in the hepatically impaired population...
For more Absorption, Distribution and Excretion (Complete) data for QUETIAPINE (8 total), please visit the HSDB record page.

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Metabolism / Metabolites
The metabolism of quetiapine occurs mainly in the liver. Sulfoxidation and oxidation are the main metabolic pathways of this drug. According to in vitro studies, cytochrome P450 3A4 metabolizes quetiapine to an inactive sulfoxide metabolite and also participates in the metabolism of its active metabolite, N-desalkyl quetiapine. CYP2D6 also regulates the metabolism of quetiapine. In one study, three metabolites of N-desalkylquetiapine were identified. Two of the metabolites were identified as N-desalkylquetiapine sulfoxide and 7-hydroxy-N-desalkylquetiapine. CYP2D6 has been found to be responsible for metabolism of quetiapine to 7-hydroxy-N-desalkylquetiapine, a pharmacologically active metabolite. Individual differences in CYP2D6 metabolism may be present, which may affect the concentrations of the active metabolite.
Quetiapine is extensively metabolized in the liver principally via sulfoxidation and oxidation to inactive metabolites. In vitro studies suggest that the cytochrome P-450 (CYP) 3A4 isoenzyme is involved in the metabolism of quetiapine to the inactive sulfoxide metabolite, which is the principal metabolite. ... Based on in vitro studies, quetiapine and 9 of its metabolites do not appear likely to inhibit CYP isoenzymes 1A2, 3A4, 2C9, 2C19, or 2D6.
Quetiapine has known human metabolites that include 7-Hydroxy Quetiapine and Quetiapine Sulfoxide.
Hepatic. The major metabolic pathways are sulfoxidation, mediated by cytochrome P450 3A4 (CYP3A4), and oxidation of the terminal alcohol to a carboxylic acid. The major sulfoxide metabolite of quetiapine is inactive. Quetiapine also undergoes hydroxylation of the dibenzothiazepine ring, O-deakylation, N-dealkylation, and phase II conjugation. The 7-hydroxy and 7-hydroxy-
N-delakylated metabolites appear to be active, but are present in very low concentrations.
Route of Elimination: Elimination of quetiapine is mainly via hepatic metabolism. Following a single oral dose of 14C-quetiapine, less than 1% of the administered dose was excreted as unchanged drug, indicating that quetiapine is highly metabolized. Approximately 73% and 20% of the dose was recovered in the urine and feces, respectively.
Half Life: 6 hours

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Biological Half-Life
The average terminal half-life of quetiapine is about 6-7 hours.
The mean terminal half-life of quetiapine is about 6 hours.

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Maternal quetiapine doses of up to 400 mg daily produce doses in milk that are less than 1% of the maternal weight-adjusted dosage. Limited long-term follow-up of infants exposed to quetiapine indicates that infants generally developed normally. A safety scoring system finds quetiapine to be possible to use during breastfeeding. Systematic reviews of second-generation antipsychotics concluded that quetiapine seemed to be the first- or second-choice agent during breastfeeding. Monitor the infant for drowsiness and developmental milestones, especially if other antipsychotics are used concurrently. Cases of galactorrhea and milk ejection have been reported rarely.
◉ Effects in Breastfed Infants
One mother took quetiapine 25 mg daily orally during pregnancy and continued to take quetiapine 50 mg daily orally during lactation. At 6 weeks the infant was doing well. No further follow-up was reported.
Another infant whose mother was taking 200 mg daily of quetiapine began to exclusively breastfeed at 8 weeks of age. The infant was developing well at 4.5 months of age and no adverse effects were reported.
A nursing mother with postpartum psychosis was started on quetiapine at 6 weeks postpartum at a dose of 25 mg daily along with unspecified benzodiazepines. The quetiapine dosage was increased gradually to 200 mg daily over the next 6 weeks and up to 300 mg daily over the ensuing 4 weeks (16 weeks postpartum). Mirtazapine 15 mg daily was also started at 8 weeks postpartum. Breastfeeding (extent not specified) was continued until 16 weeks postpartum when it was stopped because of reduced milk production. During this time, the infant was excessively drowsy until the benzodiazepine dosage was decreased at the same time as the quetiapine dosage was increased. The infant was followed for at least 2 months after breastfeeding ended and no effects on the infant's growth, motor or psychological development or signs of infant withdrawal were noted.
A nursing mother with bipolar disorder began taking 20 mg of paroxetine at 4 months postpartum and was then started on quetiapine 200 mg twice daily at 6 months postpartum. She breastfed regularly (extent not stated) and no obvious adverse effects were noted in the infant.
A woman who was treated chronically with quetiapine 400 mg and fluvoxamine 200 mg daily took the drugs throughout pregnancy and postpartum. She partially breastfed her infant (extent not stated) for 3 months from birth. No adverse events were seen and the infant developed normally.
Six nursing mothers took quetiapine in doses of 25 to 400 mg daily in addition to an antidepressant (usually paroxetine) for major depression postpartum. Their breastfed infants' development were tested at 9 to 18 months of age with the Bayley scales. Measurements were slightly low on the mental and psychomotor development scale in one infant and on the mental development scale in another. All other scores were within normal limits. The authors concluded that the low scores of the 2 infants were probably not caused by the drugs received by the infants in breastmilk.
An infant was born to a mother taking quetiapine 400 mg daily, fluoxetine 40 mg daily and oxycodone 20 mg 3 times daily. The infant was breastfed 6 to 7 times daily and was receiving 120 mcg of oral morphine 3 times daily for opiate withdrawal. Upon examination at 3 months of age, the infant's weight was at the 25th percentile for age, having been at the 50th percentile at birth. The authors attributed the weight loss to opiate withdrawal. The infant's Denver developmental score was equal to his chronological age.
One 60-week-old infant who was 50% breastfed was breastfed during maternal therapy with quetiapine 75 mg daily mg daily and venlafaxine 225 mg daily. No adverse reactions were reported by the mother or in the medical records.
A woman with bipolar disorder who delivered twins and was taking sodium valproate in a therapeutic dosage was started on quetiapine 200 mg and olanzapine 15 mg at 11 pm daily after 20 days postpartum. She withheld breastfeeding during the night and discarded milk pumped at 7 am. She then breastfed her infants until 11 pm. The mother continued feeding the infants on this schedule for 15 months. Monthly follow-up of the infants indicated normal growth and neither the pediatricians nor the parents noted any adverse effects in the infants.
A mother taking quetiapine 100 mg each night for bipolar disorder breastfed 2 successive preterm infants. Both infants were reported to be developing normally at their last follow-up visits (exact times not specified).
A woman with bipolar disorder took quetiapine 25 mg and lamotrigine 100 mg daily for the treatment of bipolar disorder during two pregnancies. After the first birth, she did not breastfeed, but she breastfed (extent not stated) the second infant. At the 2-month well baby checkup, the infant was meeting all developmental milestones.
A woman received a combination of 300 mg lamotrigine and 300 of quetiapine daily for postpartum bipolar II postpartum depression. The authors reported no major adverse reactions in her breastfed (extent not stated) infant.
An author reported 1 infant who was breastfed (extent not stated) during postpartum maternal treatment for bipolar disorder. Her quetiapine dosage was 200 mg daily. The mother reported no adverse effects in the infants.
A prospective cohort study of infants breastfed by mothers in an inpatient mother-baby psychiatric unit in India followed 2 infants who were exposed to quetiapine in breastmilk; most received partial supplementation. Neither had any short-term adverse effects. Infants were followed for 1 to 3 months after discharge and one of the infants who was also exposed to quetiapine in utero had motor and mental delay.
A woman was taking oral extended-release quetiapine 300 mg daily during the last 3 months of pregnancy and postpartum. At 3 months postpartum, her breastfed (extent not stated) infant had no apparent adverse effects and was developing normally.
Patients enlisted in the National Pregnancy Registry for Atypical Antipsychotics who were taking a second-generation antipsychotic drug while breastfeeding (n = 576) were compared to control breastfeeding patients who were not treated with a second-generation antipsychotic (n = 818). Of the patients who were taking a second-generation antipsychotic drug, 60.4% were on more than one psychotropic. A review of the pediatric medical records, no adverse effects were noted among infants exposed or not exposed to second-generation antipsychotic monotherapy or to polytherapy. The number of women taking quetiapine was not reported.
◉ Effects on Lactation and Breastmilk
Unlike the phenothiazines, quetiapine has a minimal effect on serum prolactin levels. However, galactorrhea has been reported. The maternal prolactin level in a mother with established lactation may not affect her ability to breastfeed.
Galactorrhea occurred in a woman who was not breastfeeding while she was taking venlafaxine 112.5 mg daily and quetiapine. Galactorrhea occurred 10 days after her quetiapine dose was increased to 50 mg daily a few days after starting the drug at 12.5 mg daily. Her serum prolactin level was 27.3 mcg/L (normal 2 to 30 mcg/L) and decreased to 8.5 mcg/L 2 weeks after discontinuing the drug. Galactorrhea ceased 1 week later.
Patients enlisted in the National Pregnancy Registry for Atypical Antipsychotics who were taking a second-generation antipsychotic drug while breastfeeding (n = 576) were compared to control breastfeeding patients who had primarily diagnoses of major depressive disorder and anxiety disorders, most often treated with SSRI or SNRI antidepressants, but not with a second-generation antipsychotic (n = 818). Among women on a second-generation antipsychotic, 60.4% were on more than one psychotropic compared with 24.4% among women in the control group. Of the women on a second-generation antipsychotic, 59.3% reported “ever breastfeeding” compared to 88.2% of women in the control group. At 3 months postpartum, 23% of women on a second-generation antipsychotic were exclusively breastfeeding compared to 47% of women in the control group. The number of women taking quetiapine was not reported.
A woman began using quetiapine 4 weeks postpartum for intrusive thoughts. She took her daily dose of 50 mg at 11 pm after the last nursing of the day. Every night she experienced a tingling sensation and milk ejection about 30 to 40 minutes after the dose over a period of 6 months. On one occasion she did not take the dose and the milk ejection did not occur. When she resumed the drug the next night, the milk ejection resumed. Milk ejection was probably caused by quetiapine.

[1]. J Clin Psychiatry. 2002:63 Suppl 13:5-11.

[2]. Hippocampus. 2006;16(6):551-9.

[3]. Brain Res. 2005 Nov 23;1063(1):32-9.

Quetiapine Fumarate is the fumarate salt form of quetiapine, a dibenzothiazepine derivative with antipsychotic property. Quetiapine fumarate antagonizes serotonin activity mediated by 5-HT 1A and 5-HT2 receptors. With a lower affinity, this agent also reversibly binds to dopamine D1 and D2 receptors in the mesolimbic and mesocortical areas of the brain leading to decreased psychotic effects, such as hallucinations and delusions. In addition, quetiapine fumarate also binds to other alpha-1, alpha-2 adrenergic and histamine H1 receptors.
A dibenzothiazepine and ANTIPSYCHOTIC AGENT that targets the SEROTONIN 5-HT2 RECEPTOR; HISTAMINE H1 RECEPTOR, adrenergic alpha1 and alpha2 receptors, as well as the DOPAMINE D1 RECEPTOR and DOPAMINE D2 RECEPTOR. It is used in the treatment of SCHIZOPHRENIA; BIPOLAR DISORDER and DEPRESSIVE DISORDER.
See also: Quetiapine (has active moiety).

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Quetiapine is a dibenzothiazepine, a N-alkylpiperazine and a N-arylpiperazine. It has a role as a serotonergic antagonist, a dopaminergic antagonist, a histamine antagonist, an adrenergic antagonist and a second generation antipsychotic.
Initially approved by the FDA in 1997, quetiapine is a second-generation atypical antipsychotic used in schizophrenia, major depression, and bipolar disorder. Quetiapine demonstrates a high level of therapeutic efficacy and low risk of adverse effects during long-term treatment. It is well-tolerated and a suitable option for some patients with high sensitivity to other drugs, such as [clozapine] and [olanzapine].
Quetiapine is an Atypical Antipsychotic.
Quetiapine is an atypical antipsychotic used in the treatment of schizophrenia and bipolar disorder. Use of quetiapine has been associated with serum aminotransferase elevations and in rare instances with clinically apparent acute liver injury.
Quetiapine Fumarate is the fumarate salt form of quetiapine, a dibenzothiazepine derivative with antipsychotic property. Quetiapine fumarate antagonizes serotonin activity mediated by 5-HT 1A and 5-HT2 receptors. With a lower affinity, this agent also reversibly binds to dopamine D1 and D2 receptors in the mesolimbic and mesocortical areas of the brain leading to decreased psychotic effects, such as hallucinations and delusions. In addition, quetiapine fumarate also binds to other alpha-1, alpha-2 adrenergic and histamine H1 receptors.
Quetiapine is a dibenzothiazepine derivative with antipsychotic property. Quetiapine fumarate antagonizes serotonin activity mediated by 5-HT 1A and 5-HT2 receptors. With a lower affinity, this agent also reversibly binds to dopamine D1 and D2 receptors in the mesolimbic and mesocortical areas of the brain leading to decreased psychotic effects, such as hallucinations and delusions. In addition, quetiapine also binds to other alpha-1, alpha-2 adrenergic and histamine H1 receptors.
The most common side effect is sedation, and is prescribed specifically for this effect in patients with sleep disorders. Seroquel will put the patient into a drowsy state, and will help the patient fall asleep. It is one of the most sedating of all anti psychotic drugs, rivaling even the most sedating older antipsychotics. Many prescriptions call for the entire dose to be taken before bedtime because of its sedative effects. Although quetiapine is approved by the FDA for the treatment of schizophrenia and bipolar disorder, it is frequently prescribed for off-label purposes including insomnia or the treatment of anxiety disorders. Due to its sedative side effects, reports of quetiapine abuse (sometimes by insufflating crushed tablets) have emerged in medical literature; Quetiapine belongs to a series of neuroleptics known as atypical antipsychotics, which have become increasingly popular alternatives to typical antipsychotics such as haloperidol. Quetiapine HAS approvals for the treatment of schizophrenia and acute mania in bipolar disorder. It is also used off-label to treat other disorders, such as post-traumatic stress disorder, alcoholism, obsessive compulsive disorder, anxiety disorders, hallucinations in Parkinson's disease patients using ropinirole, and as a sedative for those with sleep disorders. The most common side effect is sedation, and is prescribed specifically for this effect in patients with sleep disorders. Seroquel will put the patient into a drowsy state, and will help the patient fall asleep. It is one of the most sedating of all anti psychotic drugs, rivaling even the most sedating older antipsychotics. Many prescriptions call for the entire dose to be taken before bedtime because of its sedative effects. Although quetiapine is approved by the FDA for the treatment of schizophrenia and bipolar disorder, it is frequently prescribed for off-label purposes including insomnia or the treatment of anxiety disorders. Due to its sedative side effects, reports of quetiapine abuse (sometimes by insufflating crushed tablets) have emerged in medical literature; for the same reason, abuse of other antipsychotics, such as chlorpromazine (Thorazine), may occur as well, but research related to the abuse of typical antipsychotics is limited. for the same reason, abuse of other antipsychotics, such as chlorpromazine (Thorazine), may occur as well, but research related to the abuse of typical antipsychotics is limited.
A dibenzothiazepine and ANTIPSYCHOTIC AGENT that targets the SEROTONIN 5-HT2 RECEPTOR; HISTAMINE H1 RECEPTOR, adrenergic alpha1 and alpha2 receptors, as well as the DOPAMINE D1 RECEPTOR and DOPAMINE D2 RECEPTOR. It is used in the treatment of SCHIZOPHRENIA; BIPOLAR DISORDER and DEPRESSIVE DISORDER.
See also: Quetiapine Fumarate (has salt form).

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Drug Indication
Quetiapine is used in the symptomatic treatment of schizophrenia. In addition, it may be used for the management of acute manic or mixed episodes in patients with bipolar I disorder, as a monotherapy or combined with other drugs. It may be used to manage depressive episodes in bipolar disorder. In addition to the above indications, quetiapine is used in combination with antidepressant drugs for the treatment of major depression. Some off-label uses for this drug include the management of post-traumatic stress disorder (PTSD), generalized anxiety disorder, and psychosis associated with Parkinson's disease.
FDA Label

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Mechanism of Action
Although the mechanism of action of quetiapine is not fully understood, several proposed mechanisms exist. In schizophrenia, its actions could occur from the antagonism of dopamine type 2 (D2) and serotonin 2A (5HT2A) receptors. In bipolar depression and major depression, quetiapine's actions may be attributed to the binding of this drug or its metabolite to the norepinephrine transporter. Additional effects of quetiapine, including somnolence, orthostatic hypotension, and anticholinergic effects, may result from the antagonism of H1 receptors, adrenergic α1 receptors, and muscarinic M1 receptors, respectively.
The therapeutic effects of antipsychotic drugs are thought to be mediated by dopaminergic blockade in the mesolimbic and mesocortical areas of the CNS, while antidopaminergic effects in the neostriatum appear to be associated with extrapyramidal effects. The apparently low incidence of extrapyramidal effects associated with quetiapine therapy suggests that the drug is more active in the mesolimbic than in the neostriatal dopaminergic system. In contrast to typical antipsychotic agents (e.g., chlorpromazine) but like other atypical antipsychotic drugs (e.g., clozapine), quetiapine does not cause sustained elevations in serum prolactin concentrations and therefore is unlikely to produce adverse effects such as amenorrhea, galactorrhea, and impotence.
The exact mechanism of antipsychotic action of quetiapine has not been fully elucidated but may involve antagonism at serotonin type 1 (5-hydroxytryptamine [5- HT1A]) and type 2 (5-HT2A, 5-HT2C) receptors, and at dopamine (D1, D2) receptors. Current evidence suggests that the clinical potency and antipsychotic efficacy of both typical and atypical antipsychotic drugs generally are related to their affinity for and blockade of central dopamine D2 receptors; however, antagonism at dopamine D2 receptors does not appear to account fully for the antipsychotic effects of quetiapine. Results of in vivo and in vitro studies indicate that quetiapine is a comparatively weak antagonist at dopamine D2 receptors. Receptor binding studies show quetiapine is a weak antagonist at D1 receptors. Although their role in eliciting the pharmacologic effects of antipsychotic agents remains to be fully elucidated, dopamine D3, D4, and D5 receptors also have been identified; quetiapine possesses no affinity for the dopamine D4 receptor.
Quetiapine exhibits alpha1- and alpha2-adrenergic blocking activity; blockade of alpha1-adrenergic receptors may explain the occasional orthostatic hypotension associated with the drug. Quetiapine also blocks histamine H1 receptors, which may explain the sedative effects associated with the drug. Quetiapine possesses little or no affinity for beta-adrenergic, gamma-aminobutyric acid (GABA), benzodiazepine, or muscarinic receptors.
Recent neuroimaging and postmortem studies have reported abnormalities in white matter of schizophrenic brains, suggesting the involvement of oligodendrocytes in the etiopathology of schizophrenia. This view is being supported by gene microarray studies showing the downregulation of genes related to oligodendrocyte function and myelination in schizophrenic brain compared to control subjects. However, there is currently little information available on the response of oligodendrocytes to antipsychotic drugs (APDs), which could be invaluable for corroborating the oligodendrocyte hypothesis. In this study we found: (1) quetiapine (QUE, an atypical APD) treatment in conjunction with addition of growth factors increased the proliferation of neural progenitors isolated from the cerebral cortex of embryonic rats; (2) QUE directed the differentiation of neural progenitors to oligodendrocyte lineage through extracellular signal-related kinases; (3) addition of QUE increased the synthesis of myelin basic protein and facilitated myelination in rat embryonic cortical aggregate cultures; (4) chronic administration of QUE to C57BL/6 mice prevented cortical demyelination and concomitant spatial working memory impairment induced by cuprizone, a neurotoxin. These findings suggest a new neural mechanism of antipsychotic action of QUE, and help to establish a role for oligodendrocytes in the etiopathology and treatment of schizophrenia

C46H54N6O8S2

883.09

882.34

C, 62.56; H, 6.16; N, 9.52; O, 14.49; S, 7.26

111974-72-2

Quetiapine; 111974-69-7; Quetiapine-d4 hemifumarate; 1217310-65-0; Quetiapine sulfoxide dihydrochloride; 329218-11-3; Quetiapine hemifumarate (Standard); 111974-72-2; Quetiapine-d4 fumarate; 1287376-15-1; Quetiapine-d8 fumarate; 1185247-12-4; Quetiapine-d8 hemifumarate; Quetiapine hemifumarate-d8; 1435938-24-1; Quetiapine sulfoxide; 329216-63-9

5281025

White to off-white solid powder

556.5ºC at 760 mmHg

174-176°C

290.4ºC

3.22E-13mmHg at 25°C

4.046

4

14

14

62

615

0

C1CN(CCN1CCOCCO)C2=NC3=CC=CC=C3SC4=CC=CC=C42.C1CN(CCN1CCOCCO)C2=NC3=CC=CC=C3SC4=CC=CC=C42.C(=C/C(=O)O)\C(=O)O

ZTHJULTYCAQOIJ-WXXKFALUSA-N

InChI=1S/2C21H25N3O2S.C4H4O4/c2*25-14-16-26-15-13-23-9-11-24(12-10-23)21-17-5-1-3-7-19(17)27-20-8-4-2-6-18(20)22-21;5-3(6)1-2-4(7)8/h2*1-8,25H,9-16H2;1-2H,(H,5,6)(H,7,8)/b;;2-1+

2-[2-(4-benzo[b][1,4]benzothiazepin-6-ylpiperazin-1-yl)ethoxy]ethanol;(E)-but-2-enedioic acid

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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

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

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.66 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (5.66 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (5.66 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 0.5% CMC Na: 30mg/mL

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