5-HT_1A Receptor; 5-HT_2A Receptor; 5-HT_2B Receptor; 5-HT_2C Receptor; D₂ Receptor; D₃ Receptor; D₄ Receptor

In vitro activity: Aripiprazole exhibits strong binding affinity towards both G protein-coupled and uncoupled receptor states. Aripiprazole strongly stimulates the inhibition of cAMP accumulation mediated by D2 receptors. [1] The dopamine receptors h5-HT(2B), hD(2L) and hD(3) are the ones for which aripiprazole has the highest affinity. However, it also has significant affinity (5-30 nM) for several other 5-HT receptors, including alpha(1A)-adrenergic, hH(1)-histamine, and 5-HT(1A), 5-HT(7). Other G protein-coupled receptors such as the 5-HT(1D), 5-HT(2C), alpha(1B)-, alpha(2A)-, alpha(2B)-, alpha(2C)-, beta(1)-, and beta(2)-adrenergic, and H(3)-histamine receptors are less sensitive to apipirazole (30-200 nM). Aripiprazole functions as a partial agonist at 5-HT(2A), 5-HT(2C), D(3), and D(4) receptors in addition to being an inverse agonist at 5-HT(2B) receptors. [2]

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In vitro activity: Aripiprazole monohydrate potently stimulates the inhibition of cAMP accumulation mediated by D2 receptors[1]. Aripiprazole monohydrate exhibits a more potent anti-inflammatory effect on fractalkine, TNF-α, IL-13, and IL-17α[3].

Aripiprazole (APZ) is regarded as a first-line atypical antipsychotic used for the treatment of first and multiple episodes of schizophrenia to improve positive- and negative-symptoms. Its therapeutic indications were extended to acute manic and mixed episodes associated with bipolar disorder. In addition, APZ was approved as an adjunct therapy for major depressive disorder in 2007. Compared to other antipsychotic drugs, APZ has a unique pharmacological profile. It is a partial agonist at D₂ dopamine receptors and serotonin 5-HT(1A) and 5-HT₇ receptors, whereas it is an antagonist at serotonin 5-HT(2A) and 5-HT₆ receptors. Since epilepsy is often accompanied with neurological comorbidities such as depression, anxiety and cognitive deficits caused by both the disease and/or drug treatment, we wished to examine the effects of a sub-chronic treatment (>14 consecutive days) with APZ (0.3, 1 and 3 mg/kg; i.p.) on both absence seizures and WAG/Rij rat's behavior using different standard paradigms: Open field (OF) test, elevated plus maze (EPM) test, forced swimming (FS) test, sucrose consumption (SC) test and Morris water maze (MWM). WAG/Rij rats represent a validated genetic animal model of absence epilepsy with mild-depression comorbidity, also including other behavioral alterations. APZ treatment showed some anti-absence properties and regarding the behavioral comorbidity in this rat strain, we observed that APZ possesses clear antidepressant effects in the FS and SC tests also increasing memory/learning function in the Morris water maze test. In the two anxiety models used, APZ showed only minor effects. In conclusion, our results indicate that APZ might actually have a potential in treating absence seizures or as add-on therapy but more interestingly, these effect might be accompanied by positive modulatory actions on depression, anxiety and memory which might be also beneficial in other epileptic syndromes. This article is part of a Special Issue entitled 'Cognitive Enhancers'.[4]

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Aripiprazole monohydrate (0-3 mg/kg, IP, daily) possesses certain anxiolytic qualities[4].

Radioligand Binding Assays [2]
A large number of transiently and stably transfected cloned human cDNAs, obtained via the resources of the National Institute of Mental Health Psychoactive Drug Screening Program (NIMH-PDSP), were used for radioligand binding and functional assays as previously detailed (Rothman et al, 2000; Tsai et al, 2000). Conditions for radioligand binding assays, along with KD values for standard compounds, are listed in Table 1. In initial screening assays, Aripiprazole was tested at a concentration of 10 μM in quadruplicate at a large number of GPCRs, ion channels, and transporters. For molecular targets at which >50% inhibition was measured, Ki determinations were obtained using at least six concentrations of Aripiprazole; Ki values were calculated in quadruplicate using GraphPad Prism. [125I]DOI competition assays were performed as previously described (Choudhary et al, 1992) with the following changes: 12 dilutions of aAripiprazole spanning a range of 0.01–3000 nM were incubated with [125I]DOI (0.3 nM) in total volumes of 0.25 ml at 25°C for 1 h with 5–20 μg of membrane protein in binding buffer (50 mM Tris buffer, pH 7.4, 0.5 mM EDTA, 10 mM MgCl2). Membranes were harvested with a Brandel cell harvester by three ice-cold washes onto polyethyleneimine-pretreated (0.3%) Whatman GF/C filters. Radioactivity bound to filters was quantified by liquid scintillation counting.

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Aripiprazole is the first next-generation atypical antipsychotic with a mechanism of action that differs from currently marketed typical and atypical antipsychotics. Aripiprazole displays properties of an agonist and antagonist in animal models of dopaminergic hypoactivity and hyperactivity, respectively. This study examined the interactions of aripiprazole with a single population of human D2 receptors to clarify further its pharmacologic properties. In membranes prepared from Chinese hamster ovary cells that express recombinant D2L receptors, aripiprazole bound with high affinity to both the G protein-coupled and uncoupled states of receptors. Aripiprazole potently activated D2 receptor-mediated inhibition of cAMP accumulation. Partial receptor inactivation using the alkylating agent N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) significantly reduced the maximum effect of aripiprazole on inhibition of cAMP accumulation. This effect was seen with concentrations of EEDQ that did not alter the maximal inhibitory effect of dopamine. Consistent with the expected effects of a partial agonist, increasing concentrations of aripiprazole blocked the action of dopamine with maximal blockade equal to the agonist effect of aripiprazole alone. The efficacy of aripiprazole relative to that of dopamine varied from 25% in cells that lacked spare receptors for dopamine to 90% in cells with receptor reserve. These results, together with previous studies demonstrating partial agonist activity at serotonin 5-hydroxytryptamine (5-HT)1A receptors and antagonist activity at 5-HT2A receptors, support the identification of aripiprazole as a dopamine-serotonin system stabilizer. The receptor activity profile may underlie the unique activity of aripiprazole in animals and its antipsychotic activity in humans. [2]

Effects of Aripiprazole on cAMP Production [2]
Inhibition of forskolin-stimulated cAMP production[2]
Inhibition of forskolin-stimulated 3′,5′-cyclic adenosine monophosphate (cAMP) production in stable D4 and 5-HT1A receptor expressing cell lines was measured as previously reported (Lawler et al, 1999; Zhang et al, 1994). In brief, cells were grown in 24-well plates and growth media were replaced with fresh F12 medium containing 100 μM IBMX and 100 μM forskolin (all on ice) just prior to experimentation. Serial dilutions (10-fold) of Aripiprazole ranging from 0.1 to 10.000 nM were added to the cells, which were then incubated 20 min at 37°C and 5% CO2. The reaction was terminated by aspiration and the addition of 0.5 ml of ice-cold 3% trichloroacetic acid. Plates were chilled for 1 h at 4°C and spun at 1000 g for 15 min. cAMP was quantified using a competitive binding assay adapted with minor modifications (Nordstedt and Fredholm, 1990). For measurement of cAMP content, trichloroacetic acid extracts (40 μl) were added to reaction tubes containing cAMP assay buffer (100 mM Tris-HCl, pH 7.4, 100 mM NaCl, 5 mM EDTA). [3H]cAMP (1 nM final concentration) was added to each tube, followed by cAMP-binding proteins (approximately 100 μg of crude extract from bovine adrenal cortex in 500 μl of cAMP buffer). The reaction tubes were incubated on ice for 2 h, then harvested with a Brandel cell harvester onto Whatman GF/C filters soaked in water. Filters were allowed to dry, and bound radioactivity was quantified by liquid scintillation counting. The concentration of cAMP in each sample was estimated from a standard curve ranging from 0.1 to 100 pmol of cAMP/assay.

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Stimulation of cAMP production[2]
Studies of the effects of serotonin and Aripiprazole at 5-HT6 and 5-HT7 receptors were carried out in stable transfectants using methods previously described (Max et al, 1995; Monsma et al, 1993; Shen et al, 1993).

WAG/Rij rats (N = 6 per dose, 6 months, administration of a mixture of tiletamine/zolazepam)
0, 0.3, 1, 3 mg/kg
IP, 1 mL/kg, every day at 5 p.m. until the end of the experiments

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Sub-chronic treatment procedure [4]
Aripiprazole (APZ) was dispersed in a 1% aqueous solution (physiological saline) of Tween 80. Rats were treated intraperitoneally (i.p.) with APZ at the doses of 0.3, 1 and 3 mg/kg in a volume of 1 ml/kg injected every day at 5 p.m. until the end of the experiments. To evaluate the effects of a short-term APZ treatment (sub-chronic) on absence seizures, different groups of rats, around 6 months of age, were treated for 14 consecutive days, starting treatment one week after surgery for electrode implantation (see Section 2.3). Starting on the 15th day, rats of the sub-chronic treatment group (absence seizure evaluation) underwent three recording periods as described in Section 2.3; treatment was continued up to the last day of recordings. Control group received equal volumes of vehicle (1% Tween 80 in physiological saline). Relative to behavioral tests, no surgery was performed and treatment was continued as above reported for the entire duration of the tests without discontinuation. Therefore, the drug was always present in the system at the moment of the test. Total duration of the treatment in every test should be considered as 14 days added to day of testing; i.e. in the Morris water maze test, on day 5 recordings animals were treated for 19 consecutive days (14 + 5). In any case, APZ blood concentration can be considered stable being at the steady-state already before testing being its half-life in rats is about 1 h.

Absorption, Distribution and Excretion
Tablets: Aripiprazole tablets are well absorbed after administration, with peak plasma concentrations reached within 3 to 5 hours; the absolute oral bioavailability of the tablets is 87%. ABILIFY can be taken with or without food. Taking 15 mg ABILIFY tablets with a standard high-fat meal did not significantly affect the Cmax or AUC of aripiprazole or its active metabolite dehydroaripiprazole, but delayed the Tmax of aripiprazole by 3 hours and the Tmax of dehydroaripiprazole by 12 hours. Oral Solution: Aripiprazole solution is well absorbed orally. At the same dose, the plasma concentrations of aripiprazole solution are higher than those of the tablets. In a relative bioavailability study comparing the pharmacokinetics of 30 mg aripiprazole oral solution and 30 mg aripiprazole tablets in healthy subjects, the geometric mean Cmax and AUC values of the solution and tablets were 122% and 114%, respectively. Aripiprazole single-dose pharmacokinetics are linear and dose-proportional in the dose range of 5 mg to 30 mg. Sustained-release injectable suspension, administered every two months: Due to the low solubility of aripiprazole particles, the time to systemic circulation is prolonged after intramuscular injection in the buttock. The release characteristics of ABILIFY ASIMTUFII allow plasma drug concentrations to be maintained for more than 2 months after buttock injection. After multiple administrations, the median peak-to-trough ratio of aripiprazole after ABILIFY ASIMTUFII administration is 1.3, resulting in a flat plasma concentration curve. After multiple buttock administrations of 960 mg, the time to peak concentration (Tmax) ranges from 1 to 49 days. Following a single oral administration of [14C]-labeled aripiprazole, approximately 25% and 55% of the administered radioactive material, respectively, are recovered from urine and feces. Less than 1% of unmetabolized aripiprazole is excreted in urine, and approximately 18% of the oral dose is recovered in feces as unmetabolized form.
After intravenous administration, aripiprazole exhibits a high steady-state volume of distribution (404 L or 4.9 L/kg), indicating its extensive extravascular distribution.
The clearance of aripiprazole is estimated at 0.8 mL/min/kg. Other studies have reported clearance rates of 3297 ± 1042 mL/hr.
Oral bioavailability is 87%. Aripiprazole is well absorbed and can be taken with or without food. Concomitant administration with a high-fat meal does not affect Cmax or AUC, but delays the Tmax of aripiprazole by 3 hours and the Tmax of dehydroaripiprazole by 12 hours.
Time to peak concentration: Peak plasma concentration: 3 to 5 hours.
The high steady-state volume of distribution of aripiprazole after intravenous administration (404 L or 4.9 L/kg) indicates its extensive extravascular distribution. At therapeutic concentrations, aripiprazole and its major metabolites bind more than 99% to serum proteins, primarily albumin. In healthy volunteers, daily administration of 0.5 to 30 mg of aripiprazole showed a dose-dependent D2 receptor occupancy, indicating that aripiprazole can cross the blood-brain barrier. For more complete data on the absorption, distribution, and excretion of aripiprazole (a total of 8 metabolites), please visit the HSDB record page. Metabolites/Metabolites Aripiprazole is primarily metabolized via three biotransformation pathways: dehydrogenation, hydroxylation, and N-dealkylation. In vitro studies have shown that CYP3A4 and CYP2D6 enzymes are responsible for the dehydrogenation and hydroxylation of aripiprazole, while N-dealkylation is catalyzed by CYP3A4. Aripiprazole is the predominantly circulating drug component. At steady state, the active metabolite dehydroaripiprazole accounts for approximately 40% of the area under the plasma concentration-time curve (AUC) of aripiprazole. Aripiprazole is extensively metabolized in the liver via dehydrogenation, hydroxylation, and N-dealkylation by cytochrome P-450 (CYP) 2D6 and 3A4 isoenzymes. The major active metabolite, dehydroaripiprazole, has a similar affinity for the D2 receptor to the parent compound, accounting for approximately 40% of the area under the plasma concentration-time curve (AUC) of aripiprazole. Steady-state plasma concentrations of both aripiprazole and dehydroaripiprazole are reached within 14 days. The activity of ABILIFY is primarily attributed to the parent drug aripiprazole, followed by its major metabolite, dehydroaripiprazole. Studies have shown that dehydroaripiprazole has a similar affinity for the D2 receptor to the parent drug, and its plasma exposure accounts for 40% of the parent drug exposure.
Known metabolites of aripiprazole include dehydroaripiprazole, 4-[(2-oxo-3,4-dihydro-1H-quinoline-7-yl)oxy]butyraldehyde, 4-hydroxyaripiprazole, and 2,3-dichlorophenylpiperazine.
Aripiprazole is primarily metabolized via three biotransformation pathways: dehydrogenation, hydroxylation, and N-dealkylation. Based on in vitro studies, CYP3A4 and CYP2D6 enzymes are responsible for the dehydrogenation and hydroxylation of aripiprazole, while N-dealkylation is catalyzed by CYP3A4. Aripiprazole is the predominantly circulating drug component. At steady state, the active metabolite dehydroaripiprazole accounts for approximately 40% of the plasma AUC of aripiprazole (RxList, A308).
Elimination pathway: Less than 1% of unchanged aripiprazole is excreted in the urine, and approximately 18% of the oral dose is excreted unchanged in the feces. Half-life: 75-146 hours

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Biological Half-life
The mean elimination half-lives of aripiprazole and dehydroaripiprazole are approximately 75 hours and 94 hours, respectively. For individuals with impaired CYP2D6 metabolism, the half-life of aripiprazole is 146 hours, and these patients should take half the normal dose. Other studies have reported a half-life of aripiprazole of 61.03 ± 19.59 hours, and a half-life of its active metabolite of 279 ± 299 hours. The mean elimination half-lives of aripiprazole and dehydroaripiprazole are approximately 75 hours and 94 hours, respectively.

Hepatotoxicity

No abnormal liver function has been reported in patients taking aripiprazole long-term, but most studies do not provide serum enzyme results. Despite the widespread use of aripiprazole, only a few isolated cases of clinically significant liver injury have been reported in the literature. All reported cases were hepatocellular liver injury, occurring 1 to 3 months after treatment, with one case showing accelerated progression after re-administration. No immune allergy or autoimmune features were observed. Most cases were without jaundice, and there were no deaths or chronic injuries. Aripiprazole has not been reported in large series of drug-induced liver injury cases. The aripiprazole product label mentions reports of hepatitis and jaundice, but does not provide specific details. Therefore, clinically significant liver injury caused by aripiprazole is very rare.
Probability score: D (likely a rare cause of clinically significant liver injury).
Pregnancy and Lactation Effects

◉ Overview of Use During Lactation
Limited information suggests that low drug concentrations in breast milk are observed when mothers take up to 15 mg of aripiprazole daily. Aripiprazole can dose-dependently decrease serum prolactin levels. There have been case reports of cessation of lactation, but also cases of gynecomastia and galactorrhea. There have been reports of weight loss and poor weight gain in breastfed infants born to mothers taking aripiprazole. Until more data are available, it is recommended to prioritize other medications, especially during the breastfeeding of newborns or preterm infants.
◉ Effects on Breastfed Infants
One woman took 15 mg of aripiprazole orally daily during pregnancy and postpartum. She breastfed her infant (amount not specified), and the infant's growth and development were normal at 3 months of age.
One woman took 10 mg of aripiprazole orally daily from the 9th week of pregnancy and continued postpartum. She exclusively breastfed her infant for 6 weeks, then switched to partial breastfeeding. The infant was still breastfed at 4 months of age, with normal psychomotor and behavioral development, and reached expected developmental milestones for his/her age. A 12-day-old exclusively breastfed baby boy suffered severe weight loss and hypernatremic dehydration due to insufficient milk intake, losing 30% of his weight since birth. The infant's mother was receiving treatment for bipolar disorder, taking lamotrigine 250 mg, aripiprazole 15 mg, and sertraline 100 mg daily. She was also taking levothyroxine sodium 50 mcg once daily, as well as prenatal multivitamins and folic acid. Upon initial assessment in the emergency department, the patient presented with pallor, marbled skin, dry mucous membranes, decreased skin elasticity, and cyanosis of both feet with prolonged capillary refill time. The right foot progressively darkened, the toes turned black, and gangrene developed in the right lower extremity. Drug treatment was ineffective, ultimately requiring amputation of all five toes and metatarsal debridement. The necrosis was attributed to arterial microthrombosis caused by disseminated intravascular coagulation following severe dehydration. The authors suggest that the mother's medication regimen may have been a contributing factor to the dehydration and related problems.
A woman with paranoid schizophrenia had been receiving long-acting aripiprazole 400 mg every 28 days for 32 months prior to pregnancy. The dose was reduced to 300 mg every 28 days, and she breastfed after delivery (the extent and duration of breastfeeding were not specified). The infant was growing normally at age 3.
Patients taking second-generation antipsychotics while breastfeeding (n = 576) registered with the National Atypical Antipsychotic Pregnancy Registry were compared with a breastfeeding control group (n = 818) who did not take second-generation antipsychotics. Among the patients taking second-generation antipsychotics, 60.4% were taking more than one psychotropic drug. A review of pediatric records showed no adverse reactions in infants, regardless of whether they had been exposed to second-generation antipsychotic monotherapy or combination therapy. The number of women taking aripiprazole was not reported.
◉ Effects on Lactation and Breast Milk
Unlike phenothiazines, aripiprazole has minimal effect on serum prolactin levels and has been used to reverse hyperprolactinemia in non-lactating patients taking other antipsychotic medications. Case reports have shown reduced milk production in lactating women taking aripiprazole, as well as hyperprolactinemia and galactorrhea. For mothers who have established lactation, their prolactin levels may not affect their ability to breastfeed.
One woman started taking 10 mg of aripiprazole daily at 20 weeks of gestation. She delivered at full term via cesarean section but failed to establish lactation. The authors believe that more data are needed to determine whether aripiprazole has adverse effects on lactation.
One woman started taking 10 mg of aripiprazole orally daily from 9 weeks of gestation and continued postpartum. She exclusively breastfed her infant for 6 weeks but then began supplementing with formula due to insufficient milk production. Her serum prolactin level was 35 to 40 μg/L, lower than expected for lactating mothers. The authors speculate that aripiprazole may have caused her low serum prolactin levels and reduced milk production. A woman with bipolar disorder took lithium during pregnancy and postpartum. Ten days postpartum, her infant's serum lithium level was 0.26 mmol/L, so lithium was discontinued. Quetiapine was started, but discontinued due to sedation in the mother. Aripiprazole was started at 2.5 mg daily, and within 24 hours, the mother noticed a significant decrease in milk production. After two weeks of working with a lactation consultant, she still faced breastfeeding difficulties and restarted lithium. Within 48 hours, her milk production significantly improved. A retrospective study included outpatients taking an average of 17.3 mg of aripiprazole daily (n=20) or other antipsychotic medications (n=141). The results showed that 81% of patients taking such high doses of aripiprazole experienced hypoprolactinemia, compared to only 2.9% of patients not receiving aripiprazole.
A breastfeeding mother with a 5-week-old infant was diagnosed with bipolar disorder, panic attacks, and anxiety. She started taking hydroxyzine 50 mg for an unknown period of time, lasting 3 to 5 days, but it did not affect her milk production. She then started taking aripiprazole 5 mg for an unknown period of time. After 5 days, she reported a decrease in milk production and the need for formula supplementation. Nine days after discontinuing both medications, her milk production returned to normal. The decrease in breast milk production was likely caused by the medications, most likely aripiprazole.
A woman with chronic depression took extended-release venlafaxine 225 mg daily throughout her pregnancy. She delivered by cesarean section at 36.5 weeks of gestation and began breastfeeding. The baby did not suckle sufficiently, but the mother expressed milk after each feeding to supplement. It was estimated that she produced at least 900 ml of milk per day. Eight days postpartum, she began experiencing depressive symptoms and started taking aripiprazole 2 mg daily, which she had been taking before pregnancy. Three days after starting the combined medication regimen, she noticed a decrease in breast milk production, and lactation ceased completely within 21 days. Aripiprazole, or its combination with venlafaxine, can both lead to a decrease in breast milk production.
A woman with major depressive disorder was taking duloxetine 40 mg twice daily. Two weeks later, she experienced menstrual irregularities and nipple discharge. Her serum prolactin level rose to 205 mcg/L. The duloxetine dose was reduced to 60 mg once daily, and aripiprazole was started at an initial dose of 2.5 mg daily, subsequently increased to 5 mg daily. Within two weeks, the galactorrhea stopped, and her serum prolactin level dropped to 118 mcg/L. Six weeks later, her serum prolactin level was 39 mcg/L. This combined medication regimen was continued for 39 weeks without further galactorrhea.
A postpartum woman was taking sertraline 200 mg daily due to anxiety, depressive symptoms, hypochondria, and compulsive checking behaviors (affecting parent-child relationships). Two months later, aripiprazole was added at 5 mg daily. Two to three days later, the patient reported a decrease in milk production. Prolactin levels decreased from 30.18 mcg/L to 5.02 mcg/L. Milk production returned to normal within a week of discontinuing aripiprazole.
Patients taking second-generation antipsychotics while breastfeeding (n = 576) registered with the National Registry for Atypical Antipsychotic Pregnancy were compared with a control group of breastfeeding patients primarily diagnosed with major depressive disorder and anxiety (n = 818). The control group of breastfeeding patients most commonly received SSRIs or SNRIs but did not use second-generation antipsychotics. Among women taking second-generation antipsychotics, 60.4% were taking more than one psychotropic medication concurrently, compared to 24.4% in the control group. Among women taking second-generation antipsychotics, 59.3% reported having breastfed, compared to 88.2% in the control group. Three months postpartum, 23% of women taking second-generation antipsychotic medications exclusively breastfed, compared to 47% in the control group. No reports were found regarding the number of women taking aripiprazole. Two women took aripiprazole to treat schizophrenia during pregnancy and postpartum at daily doses of 10 mg and 20 mg, respectively. Neither mother was able to breastfeed due to minimal or no milk production. What is aripiprazole? Aripiprazole is a medication used to treat schizophrenia, bipolar disorder, autism spectrum disorder, and depression. Some brand names for aripiprazole include Abilify®, Abilify Discmelt®, Aristada®, and Abilify Maintena®. Sometimes, when people find out they are pregnant, they consider changing their medication regimen or even stopping it entirely. However, it is essential to talk to your healthcare provider before making any changes. Your healthcare provider can discuss the benefits of treating your condition and the risks of not treating it during pregnancy. For more information on depression, please see our fact sheet: https://mothertobaby.org/fact-sheets/depression-pregnancy/.
◈ I am taking aripiprazole. Will it affect my ability to get pregnant?
There is currently no research showing whether taking aripiprazole affects pregnancy.
◈ Does taking aripiprazole increase the risk of miscarriage?
Miscarriage is common and can occur in any pregnancy for a variety of reasons. It is currently unclear whether aripiprazole increases the risk of miscarriage. One study on aripiprazole use during pregnancy reported an increased risk of miscarriage, but other studies have not reported this result. However, some studies report that the risk of miscarriage is higher if prenatal depression is left untreated. Because there are many causes of miscarriage, it is difficult to determine whether it is caused by medication, an underlying medical condition, or other factors.
◈ Does taking aripiprazole increase the risk of birth defects?
There is a 3-5% risk of birth defects in every pregnancy, known as background risk. Information on aripiprazole use during pregnancy is limited. Three small studies and one large study did not show that taking aripiprazole during pregnancy increases the risk of birth defects.
◈ Does taking aripiprazole during pregnancy increase the risk of other pregnancy-related problems?
It is currently unclear whether aripiprazole causes other pregnancy-related problems such as preterm birth (delivery before 37 weeks of gestation) or low birth weight (birth weight less than 5 pounds 8 ounces [2500 grams]). Some studies have reported that taking aripiprazole may slightly increase the risk of preterm birth and lower-than-expected birth weight. These studies involved short-term use of aripiprazole. However, underlying medical conditions being treated may also increase the risk of these pregnancy complications.
◈ I need to take aripiprazole throughout my pregnancy. Will it cause my baby to experience withdrawal symptoms after birth?
There have been reports of some infants who were exposed to aripiprazole in late pregnancy developing symptoms shortly after birth. These symptoms, sometimes called withdrawal symptoms, may include irritability, difficulty breathing, tremors, lethargy, difficulty feeding, muscle stiffness, or hypotonia. Information on this is limited, and it is unclear whether the probability of this happening is high or low. Some babies' symptoms will disappear quickly, while others may require hospitalization. Not all babies exposed to aripiprazole will develop these symptoms. It is important to inform your healthcare provider that you are taking aripiprazole so that your baby can receive optimal care if symptoms occur.
◈ Will taking aripiprazole during pregnancy affect a child's future behavior or learning?
It is unclear whether aripiprazole increases the risk of behavioral or learning problems in a child. However, an underlying medical condition being treated may also affect a child's behavior or development.
◈ Breastfeeding while taking aripiprazole:
Limited research suggests that when breastfeeding women take no more than 15 mg of aripiprazole daily, a small amount of the drug may pass into breast milk. While some babies may experience drowsiness, most breastfed babies exposed to aripiprazole do not report any symptoms. If you suspect your baby has any symptoms (such as drowsiness or difficulty feeding), contact your child's healthcare provider immediately. Aripiprazole may reduce the amount of breast milk your body produces. Please consult your healthcare provider with any questions regarding breastfeeding.
◈ Will aripiprazole affect fertility or increase the risk of birth defects if the man takes it?
Currently, no studies have assessed whether aripiprazole affects male fertility (the ability to impregnate a partner) or increases the risk of birth defects (above background risk). Generally, contact with the father or sperm donor is unlikely to increase the risk of pregnancy. For more information, please see the “Father Contact” information sheet on the MotherToBaby website at https://mothertobaby.org/fact-sheets/paternal-exposures-pregnancy/.

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Protein Binding
At therapeutic concentrations, aripiprazole and its major metabolites bind to serum proteins in more than 99% of cases, primarily albumin.

[1]. Aripiprazole, a novel antipsychotic, is a high-affinity partial agonist at human dopamine D2 receptors. J Pharmacol Exp Ther. 2002 Jul;302(1):381-9.

[2]. Aripiprazole, a novel atypical antipsychotic drug with a unique and robust pharmacology. Neuropsychopharmacology. 2003 Aug;28(8):1400-11.

[3]. Aripiprazole as a Candidate Treatment of COVID-19 Identified Through Genomic Analysis. Front Pharmacol. 2021 Mar 2;12:646701.

[4]. Ameliorating effects of aripiprazole on cognitive functions and depressive-like behavior in a genetic rat model of absence epilepsy and mild-depression comorbidity. Neuropharmacology. 2013 Jan;64:371-9.

[5]. Aripiprazole: a novel atypical antipsychotic drug with a uniquely robust pharmacology. CNS Drug Rev. 2004 Winter;10(4):317-36.

Aripiprazole is an N-arylpiperazine compound in which the piperazine ring is substituted at the 1-position with a 4-[(2-oxo-1,2,3,4-tetrahydroquinoline-7-yl)oxy]butyl group and at the 4-position with a 2,3-dichlorophenyl group. It is an antipsychotic drug used to treat schizophrenia and other mood disorders. It has multiple functions, including H1 receptor antagonist, serotonergic agonist, second-generation antipsychotic, and drug metabolite. It belongs to the quinolone, N-arylpiperazine, N-alkylpiperazine, dichlorobenzene, aromatic ether, and δ-lactam classes. Aripiprazole is an atypical antipsychotic drug, used orally to treat schizophrenia, type I bipolar disorder, major depressive disorder, autism-related irritability, and Tourette syndrome. It is also indicated for the treatment of agitation associated with manic episodes in schizophrenia or bipolar disorder. Aripiprazole works by activating dopaminergic and 5-HT1A receptors, and antagonizing alpha-adrenergic and 5-HT2A receptors. Aripiprazole was approved by the U.S. Food and Drug Administration (FDA) on November 15, 2002. Aripiprazole is an atypical antipsychotic drug. It is used to treat schizophrenia and bipolar disorder. No consistent association has been found between aripiprazole treatment and elevated serum transaminases, nor has it been associated with clinically significant cases of acute liver injury. Aripiprazole is a quinoline derivative and also an atypical antipsychotic drug. It has partial agonist activity against dopamine D2 and serotonin 5-HT1A receptors, while exhibiting potent antagonism against serotonin 5-HT2A receptors. This drug stabilizes dopamine and serotonin activity in the limbic and cortical systems. Aripiprazole is used to treat schizophrenia and acute manic and mixed episodes associated with type I bipolar disorder. Aripiprazole is an atypical antipsychotic drug used to treat schizophrenia. It has also recently received FDA approval for the treatment of acute manic and mixed episodes associated with bipolar disorder. Aripiprazole appears to exert its antipsychotic effect primarily through partial agonist activity on D2 receptors. In addition to its partial agonist activity on D2 receptors, aripiprazole is also a partial agonist of 5-HT1A receptors and, like other atypical antipsychotics, exhibits antagonist activity on 5-HT2A receptors. Aripiprazole has moderate affinity for histamine and alpha-adrenergic receptors, but no significant affinity for cholinergic muscarinic receptors. Aripiprazole is a piperazine and quinolone derivative primarily used as an antipsychotic. It is a partial agonist of 5-HT1A and dopamine D2 receptors, while also acting as an antagonist postsynaptic, and is also an antagonist of 5-HT2A receptors. It is used to treat schizophrenia and bipolar disorder, and as adjunctive therapy for depression.
See also: aripiprazole lorazepam (active ingredient); aripiprazole carvomethazine (active ingredient); aripiprazole monohydrate (note moved to).

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Drug Indications
Aripiprazole is indicated for the treatment of acute manic episodes and mixed episodes associated with bipolar I disorder, irritability associated with autism spectrum disorder, schizophrenia, and Tourette syndrome. It may also be used as adjunctive therapy for major depressive disorder. [L45859 Aripiprazole injection is indicated for the treatment of agitation associated with schizophrenia or bipolar mania. Finally, aripiprazole extended-release injection (injected every two months) is approved for the treatment of schizophrenia in adults and for maintenance therapy of bipolar I disorder in adults.
FDA Label
Aripiprazole manufactured by Mylan Pharmaceuticals is indicated for the treatment of schizophrenia in adults and adolescents aged 15 years and older. Mylan Pharma's aripiprazole is indicated for the treatment of moderate to severe manic episodes in bipolar I disorder, and for the prevention of new manic episodes in adult patients with a history of predominantly manic episodes who have responded to aripiprazole treatment. Aripiprazole (Mylan Pharma) is indicated for the treatment of moderate to severe manic episodes in adolescents aged 13 years and older with bipolar I disorder, with a maximum treatment duration of 12 weeks. It is also indicated for maintenance treatment of stable adult schizophrenia patients treated with oral aripiprazole. Aripiprazole (Sandoz) is indicated for the treatment of schizophrenia in adolescents aged 15 years and older and adults. Aripiprazole (Sandoz) is indicated for the treatment of moderate to severe manic episodes in bipolar I disorder, and for the prevention of new manic episodes in adult patients with a history of predominantly manic episodes who have responded to aripiprazole treatment. Aripiprazole (Sandoz) is indicated for the treatment of moderate to severe manic episodes in adolescents aged 13 years and older with bipolar I disorder, with a maximum treatment duration of 12 weeks.
Aripiprazole (Zentiva) is indicated for the treatment of schizophrenia in adults and adolescents aged 15 years and older. Zentiva is also indicated for the treatment of moderate to severe manic episodes in type I bipolar disorder, and for the prevention of recurrent manic episodes in adult patients with a history of predominantly manic episodes who have responded to aripiprazole treatment. Zentiva is indicated for the treatment of moderate to severe manic episodes in adolescents aged 13 years and older, with a treatment duration of up to 12 weeks.
Aripiprazole (Accord) is indicated for the treatment of schizophrenia in adults and adolescents aged 15 years and older. Accord is indicated for the treatment of moderate to severe manic episodes in type I bipolar disorder, and for the prevention of recurrent manic episodes in adult patients with a history of predominantly manic episodes who have responded to aripiprazole treatment. Accord is also indicated for the treatment of moderate to severe manic episodes in adolescents aged 13 years and older with type I bipolar disorder, with a treatment duration of up to 12 weeks. Aripiprazole (Abcord) is indicated for the treatment of schizophrenia in adolescents and adults aged 15 years and older. It is also indicated for the treatment of moderate to severe manic episodes in type I bipolar disorder, and for the prevention of recurrent manic episodes in adult patients with a history of predominantly manic episodes who have responded to aripiprazole treatment. Aripiprazole is indicated for the treatment of moderate to severe manic episodes in adolescents aged 13 years and older with bipolar I disorder, with a treatment duration of up to 12 weeks.
Treatment of bipolar disorder, treatment of schizophrenia

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Mechanism of action
The antipsychotic effect of aripiprazole may be related to its partial agonistic effect on D2 and 5-HT1A receptors and its antagonistic effect on 5-HT2A receptors; however, the exact mechanism is not fully elucidated. One proposed mechanism is that aripiprazole, when binding to D2 receptors, both stimulates and inhibits dopamine. Under high dopamine concentrations, it reduces the firing frequency of dopaminergic neurons; while under low dopamine concentrations, it increases the firing frequency of dopaminergic neurons. Aripiprazole's partial agonist activity places its tonicity on dopaminergic neurons between that of a full agonist and antagonist of the D2 receptor. Furthermore, some adverse effects may be related to its effects on other receptors. For example, orthostatic hypotension may be due to its antagonism of adrenergic α1 receptors. The antipsychotic mechanism of aripiprazole is not fully elucidated, but similar to other atypical antipsychotics (e.g., piracetam, risperidone, ziprasidone), it may involve its activity on dopamine D2 receptors as well as serotonin type 1A (5-HT1A) and type 2 (5-HT2A) receptors. However, aripiprazole differs from other atypical antipsychotics in that it exhibits partial agonist activity on D2 and 5-HT1A receptors, while exhibiting antagonist activity on 5-HT2A receptors. Antagonistic effects of aripiprazole on other receptors (e.g., α1-adrenergic receptors, histamine H1 receptors) may lead to other therapeutic effects and adverse effects (e.g., orthostatic hypotension, drowsiness).
…Aripiprazole exhibits typical antagonistic activity against dopamine (D2) receptors in the mesolimbic pathway, while also possessing unique partial agonist activity against D2 receptors in the mesocortical pathway. Like other atypical antipsychotics, aripiprazole has strong antagonistic activity against 5-HT (2a) receptors and, similar to ziprasidone, also exhibits agonist activity against 5-HT (1a) receptors. Among atypical antipsychotics, aripiprazole has the lowest affinity for α1-adrenergic (α1), histamine (H1), and muscarinic (M1) receptors. This combined effect may explain its efficacy in treating both positive and negative symptoms of schizophrenia and bipolar disorder. …Other early data suggest that aripiprazole may reduce plasma prolactin levels, as well as plasma glucose and lipid levels…

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Atypical antipsychotics have revolutionized the treatment of schizophrenia and related disorders. Currently approved atypical antipsychotics are characterized by relatively low affinity for the D(2) dopamine receptor and relatively high affinity for the 5-HT(2A) serotonin receptor (5-HT, serotonin). Aripiprazole (OPC-14597) is a novel atypical antipsychotic reported as a high-affinity partial agonist of the D(2) dopamine receptor. We now present a comprehensive pharmacological profile of aripiprazole on a large number of cloned G protein-coupled receptors, transporters, and ion channels. These data reveal several interesting and potentially important molecular targets for which aripiprazole has affinity. Aripiprazole exhibits the highest affinity for h5-HT(2B), hD(2L), and hD(3) receptors, but also shows significant affinity (5–30 nM) for several other 5-HT receptors (5-HT(1A), 5-HT(2A), and 5-HT(7) receptors), as well as α(1A) adrenergic receptors and hH(1) histamine receptors. Aripiprazole has lower affinity (30–200 nM) for other G protein-coupled receptors, including 5-HT1D, 5-HT2C, α1B, α2A, α2B, α2C, β1 and β2 adrenergic receptors, and H3 histamine receptors. Functionally, aripiprazole is an inverse agonist of the 5-HT2B receptor and exhibits partial agonist activity against the 5-HT2A, 5-HT2C, D3, and D4 receptors. Interestingly, we also found that aripiprazole's functional action on the cloned human D(2)-dopamine receptor is cell-type selective, and depending on the cell type and function examined, it may exhibit a range of effects (e.g., agonist, partial agonist, antagonist) on the cloned D(2)-dopamine receptor. This mixed functional action on the D(2)-dopamine receptor is consistent with the hypothesis proposed by Lawler et al. (1999) that aripiprazole has a "functionally selective" effect. In summary, our results support the hypothesis that the unique role of aripiprazole in the human body is likely the result of “functionally selective” activation of the D(2) (and possibly D(3))-dopamine receptor, as well as important interactions with certain other biogenic amine receptors, particularly 5-HT receptor subtypes (5-HT(1A), 5-HT(2A)). [2]

C23H29CL2N3O3

466.4007

465.159

C, 59.23; H, 6.27; Cl, 15.20; N, 9.01; O, 10.29

851220-85-4

Aripiprazole; 129722-12-9; Aripiprazole-d8; 1089115-06-9; 851220-85-4 (hydrate); 1259305-26-4 (cavoxil); 1259305-29-7 (lauroxil)

11408688

Solid powder

4.883

2

5

7

31

559

0

ClC1C(=C([H])C([H])=C([H])C=1N1C([H])([H])C([H])([H])N(C([H])([H])C([H])([H])C([H])([H])C([H])([H])OC2C([H])=C([H])C3=C(C=2[H])N([H])C(C([H])([H])C3([H])[H])=O)C([H])([H])C1([H])[H])Cl.O([H])[H]

UXQBDXJXIVDBTF-UHFFFAOYSA-N

InChI=1S/C23H27Cl2N3O2.H2O/c24-19-4-3-5-21(23(19)25)28-13-11-27(12-14-28)10-1-2-15-30-18-8-6-17-7-9-22(29)26-20(17)16-18;/h3-6,8,16H,1-2,7,9-15H2,(H,26,29);1H2

7-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butoxy]-3,4-dihydro-1H-quinolin-2-one;hydrate

OPC 31; OPC14597; OPC-31; OPC 14597; Aripiprazole monohydrate; Aripiprazole hydrate; 851220-85-4; UNII-O362MEQ7VR; O362MEQ7VR; Aripiprazole (monohydrate); Aripiprazole hydrate (JAN); ARIPIPRAZOLE HYDRATE [JAN]; OPC31; Abilitat; OPC-14597

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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