5-HT₇ Receptor ( IC50 = 0.495 nM ); 5-HT_1A Receptor ( IC50 = 6.75 nM ); D₂ Receptor ( IC50 = 1.68 nM )

In vitro activity: Lurasidone inhibits the binding of [35S]GTPγS at the human dopamine D2L receptor in a concentration-dependent manner with a KB value of 2.8 nM. Lurasidone, at a KB value of 2.6 nM, counteracts the accumulation of cAMP induced by 5-HT in CHO/h5-HT7 cells. Lurasidone has a maximum effect of 33% and partially stimulates [35S]GTPγS binding to the human 5-HT1A receptor membrane preparation. In the rat frontal cortex and striatum, lorazidone dose-dependently raises the ratio of DOPAC/dopamine.

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To investigate whether iloperidone and Lurasidone affect the activity of CYP enzymes, the probe reaction assays were conducted with varied concentration of the neuroleptics. The Dixon`s plots of the metabolism of CYP-specific substrates, carried out in human liver microsomes and supersomes CYP1A2, CYP2D6, CYP2C9, CYP2C19 and CYP3A4, in the absence or presence of the tested neuroleptics, showed that the examined neuroleptics exerted inhibitory effects on different CYP enzymes. However, their potency to inhibit specific CYP enzymes was diverse. Iloperidone exerted a strong inhibitory effect on the activity of CYP3A4 (Ki = 0.38 and 0.3 µM in liver microsomes and supersomes, respectively) and CYP2D6 (Ki = 2.9 and 10 µM in liver microsomes and supersomes, respectively). Moreover, iloperidone attenuated the activity of CYP2C19 (Ki = 6.5 and 32 µM in liver microsomes and supersomes, respectively) and CYP1A2 (Ki = 45 and 31 µM in liver microsomes and supersomes, respectively). Iloperidone did not affect the activity of CYP2C9. In comparison, Lurasidone moderately inhibited CYP1A2 (Ki = 12.6 and 15.5 µM in liver microsomes and supersomes, respectively), CYP2C9 (Ki = 18 and 3.5 µM in liver microsomes and supersomes, respectively), CYP2C19 (Ki = 18 and 18.4 µM in liver microsomes and supersomes, respectively) and CYP3A4 (Ki = 29.4 and 9.1 µM in liver microsomes and supersomes, respectively). Lurasidone weakly diminished the activity of CYP2D6 (Ki = 37.5 and 85 µM in liver microsomes and supersomes, respectively).[3]
Lineweaver–Burk’s plots referring to the kinetics of enzyme inhibition suggested that in both human liver microsomes and supersomes iloperidone inhibited the activity of CYP3A4 via a noncompetitive mechanism, CYP2D6 via a competitive mechanism, CYP1A2 and CYP2C19 via a mixed mechanism (inserts in Figs. 1, 3, 4, 5). On the other hand, Lurasidone inhibited the activity of CYP1A2, CYP2C9 and CYP2C19 via a mixed mechanism, CYP3A4 and CYP2D6 via a competitive mechanism (inserts in Figs. 1, 2, 3, 4, 5. The Ki values and mechanisms of inhibition of major human CYP enzyme activities by iloperidone and Lurasidone are summarized in Table 1 [1].

Lurasidone's inhibitory effects on MAP-induced hyperactivity last longer than eight hours. At one, two, four, and eight hours following treatment, the corresponding ED50 values of the action are 2.3 mg/kg, 0.87 mg/kg, 1.6 mg/kg, and 5.0 mg/kg. In rats with an ED50 of 6.3 mg/kg, lurasidone (1 mg/kg–10 mg/kg) dose-dependently inhibits the conditioned avoidance response. Rats treated with lurasidone (ED50 = 5.6 mg/kg) or 3.0 mg/kg show dose-dependent inhibition of TRY-induced forepaw clonic seizure and p-CAMP-induced hyperthermia, respectively. In the Vogels conflict test, rats given a MED of 10 mg/kg receive a dose-dependent and statistically significant increase in the number of shocks (0.3 mg/kg–30 mg/kg). In rats with olfactory bulbectomy models, luerasdone (3 mg/kg, 2 weeks) dramatically reduces hyperactive behavior. The duration of the loss of righting reflexes in mice induced by hexobarbital (anesthesia) is slightly prolonged by luridodone (700 mg/kg–1000 mg/kg) in a dose-dependent manner. The MK-801-induced impairment of rats' passive-avoidance response is significantly and dose-dependently reversed by luerisdone (30 mg/kg, p.o.). In rats, MK-801-induced learning impairment in the Morris water maze test is potently reversed by luerasdone (3 mg/kg p.o.). By using the radial-arm maze test, lurasidone (3 mg/kg p.o.) potently reverses the reference memory impairment caused by MK-801 and moderately, but not significantly, attenuates the working memory impairment caused by MK-801. In the rat prefrontal cortex and, to a lesser extent, the hippocampus, lorisidone (10 mg/kg) treatment raises total BDNF mRNA levels. Without affecting the protein levels of neurotrophin (precursor and mature forms) in hippocampal extracts, luerisdone (10 mg/kg) dramatically raises the levels of mature BDNF protein in the rat prefrontal cortex.

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Lurasidone (SM-13496) is a novel atypical antipsychotic with high affinities to dopamine D2, serotonin 5-HT7, 5-HT2A, 5-HT1A receptors and α2C adrenoceptor. In this study, the effects of lurasidone on the rat passive-avoidance response and its impairment by the N-methyl-d-aspartate (NMDA) receptor antagonist MK-801 (dizocilpine) were evaluated and compared with those of other antipsychotics. The passive-avoidance response was examined by measuring the step-through latency, 1 day after the animals received foot-shock training. When given before the training session, lurasidone did not affect the passive-avoidance response at any dose tested (1–30 mg/kg, p.o.). All the other atypical antipsychotics examined (i.e., risperidone, olanzapine, quetiapine, clozapine and aripiprazole), however, significantly reduced the step-through latency at relatively high doses. A pre-training administration of lurasidone significantly and dose-dependently reversed the MK-801-induced impairment of the passive-avoidance response. At doses lower than those that affected the passive-avoidance response, risperidone, quetiapine, and clozapine partially reduced the MK-801-induced impairment, whereas haloperidol, olanzapine, and aripiprazole were inactive. In addition, the post-training administration of lurasidone was as effective in countering the MK-801 effect as the pre-training administration, suggesting that lurasidone worked, at least in part, by restoring the memory consolidation process disrupted by MK-801. These results suggest that lurasidone is superior to other antipsychotics in improving the MK-801-induced memory impairment and may be clinically useful for treating cognitive impairments in schizophrenia. [2]

In Vitro Receptor Binding Profile [1]
As shown in Table 2, in vitro receptor binding experiments revealed that Lurasidone demonstrates affinity for dopamine D2 and 5-HT2A receptors higher than other tested antipsychotics. In contrast to other agents, lurasidone also displayed high affinity for 5-HT7, 5-HT1A, and noradrenaline α2C receptors (Ki values, 0.495, 6.75, and 10.8 nM, respectively). Lurasidone had lower affinity for noradrenergic α1 and α2A receptors (Ki values 47.9 and 40.7 nM, respectively) and only negligible affinities...

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Determination of CYP enzyme activities [3]
To study the inhibitory effects of iloperidone and Lurasidone on the activity of various CYP isoforms, pooled human liver microsomes and microsomes from baculovirus-infected insect cells expressing human CYPs (supersomes) were used. The following probe reactions were applied, according to the methods previously described: caffeine 3-N-demethylation for CYP1A2 (caffeine 200, 400 and 800 µM), diclofenac 4′-hydroxylation for CYP2C9 (diclofenac 5, 10, 25 µM), perazine N-demethylation for CYP2C19 (perazine 50, 100, 200 µM), bufuralol 1′-hydroxylation for CYP2D6 (bufuralol 10, 25, 50 µM), and testosterone 6β-hydroxylation for CYP3A4 (50, 100 and 200 µM). Incubation systems for CYP2C9, 2C19 and 3A4 contained: 50 mM TRIS/KCL buffer (pH = 7.4), NADPH generating system (1 mM NADP, 5 mM glucose 6-phosphate, 1.7 U/ml glucose 6-phosphate dehydrogenase, 1 mM EDTA and 3 mM MgCl2). Incubation mixture for CYP1A2 included: 0.15 M phosphate buffer (pH = 7.4) and 1 mM NADPH, and for CYP2D6: 0.1 M TRIS/KCL buffer (pH = 7.4), NADPH generating system (1.3 mM NADP, 3.3 mM glucose 6-phosphate, 1 U/ml glucose 6-phosphate dehydrogenase and 3.3 mM MgCl2). The appropriate concentrations of human liver microsomes (0.5 mg/ml for each reaction) or supersomes (50 pmol CYP/ml), various concentrations of a probe substrate in the absence or presence of neuroleptic (concentrations: 0.1, 0.5, 1, 5, 10 µM) were added, The final volume of the reaction mixture was 0.5 ml. The incubation time for supersomes was 30 min (for each reaction) and for liver microsomes: 30 min (diclofenac 4′-hydroxylation and bufuralol 1′-hydroxylation), 20 min (perazine N-demethylation and testosterone 6β-hydroxylation) or 50 min (caffeine 3-N-demethylation). After the reactions had been stopped, the concentrations of specific substrates and their metabolites formed in liver microsomes or supersomes were assessed by the HPLC method with UV detection (or fluorimetric detection for CYP2D6), as described previously.

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Determination of kinetic parameters, Ki values and the mechanism of inhibition [3]
Kinetic parameters (Km, Vmax, Ki) describing the course of CYP-specific reactions in liver microsomes or supersomes were obtained using the Michaelis–Menten approach and a non-linear regression analysis. The inhibitory effects of iloperidone and Lurasidone on CYP enzymes are presented graphically as Dixon’s plots (1/V against I) indicating Ki values, and Lineweaver–Burk’s plots (1/V against 1/S) showing the mechanism of inhibition (competitive inhibition increases the Km value, not affecting the Vmax value; non-competitive inhibition decreases the Vmax value, not affecting the Km value; mixed inhibition entails respective changes in both the Km and Vmax values).

Methamphetamine (MAP) (1 mg/kg i.p.) is injected into each individual SD rat in a clear plastic cage one hour after the drugs or vehicle are administered. One, two, four, and eight hours prior to the MAP injection, luerazone (hydrochloride) (SM-13496 (hydrochloride)) is given as part of the persistence of effect test. Following a 10-minute MAP injection, locomotor activity is monitored for 80 minutes. The ED50 value, which inhibits MAP-induced hyperactivity by 50% of the animals tested, is determined using four or five groups of six to thirteen rats.[1]

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Lurasidone hydrochloride, haloperidol, olanzapine, aripiprazole, risperidone, quetiapine hemifumarate, and clozapine were prepared. The previously reported anti-dopamine ED50 values (mg/kg, p.o.) were used to adjust the test dosage of each antipsychotic drug to a level expected to block dopamine D2 receptors in vivo, i.e., 1–30 mg/kg p.o. for Lurasidone and quetiapine; 0.3 and 1 mg/kg p.o. for haloperidol; 0.3–3 mg/kg for risperidone; 0.3–10 mg/kg for olanzapine and aripiprazole; and 0.3–30 mg/kg p.o. for clozapine (Hirose et al., 2004, Migler et al., 1993, Moore et al., 1992, Sakamoto et al., 1997). All the antipsychotic drugs were dissolved or suspended in 0.5% methylcellulose (MC) as the vehicle, and orally administered at a volume of 5 ml/kg. In the cases in which Lurasidone was injected intravenously, the drug was dissolved in 25% polyethylene glycol, and injected at 1 ml/kg into the tail vein. In this case, anti-dopaminergic doses of 0.1 and 0.3 mg/kg, which effectively antagonize methamphetamine-induced hyperactivity in rats (data not shown), were used. (+)-MK-801 hydrogen maleate was dissolved in saline and injected subcutaneously at a volume of 5 ml/kg. All the test drugs and MK-801 were prepared on the day of the experiment. All other agents were obtained from commercial sources.[2]

We performed 3 sets of studies as described below.
Study 1:
As previously reported for clozapine and olanzapine (Ninan and Kulkarni, 1996, Rasmussen et al., 2001), some antipsychotic drugs may impair passive-avoidance learning when administered alone before the training session. Therefore, we first investigated the effects of Lurasidone and other antipsychotic drugs on the acquisition of the passive-avoidance response, when administered alone without giving MK-801. Antipsychotic drugs or the vehicle MC was administered orally 1 h before the passive-avoidance training. Ten to 15 rats per dose group were used. The data from this study were used to determine dosages of antipsychotic drugs that did not impair the passive-avoidance response.

Study 2:
We next examined the effect of Lurasidone on MK-801-induced deficits in the passive-avoidance response and compared the results with those of the other antipsychotic drugs. A pre-training injection of MK-801 is known to induce state-dependency in some of the context-dependent responses such as the passive avoidance in rats, which apparently impairs the retrieval of acquired response unless a pre-test injection of MK-801 is also given to rats (Harrod et al., 2001, Jackson et al., 1992, Schmidt et al., 1999). In this study, therefore, we gave both pre-training and pre-test injections of MK-801 to avoid the state-dependent influence with MK-801, according to the procedures as previously used in the passive-avoidance test (Harrod et al., 2001, Nakagawa and Iwasaki, 1996). In addition, a relatively low dose of MK-801 (0.05 mg/kg, s.c.) that reportedly does not affect motor functions and the passive-avoidance retrieval with the pre-test injection (Nakagawa and Iwasaki, 1996, Venable and Kelly, 1990) was employed. The antipsychotic drugs were administered 1 h before the training session at doses that did not impair the passive-avoidance response in Study 1. Twenty to 25 rats per dose group were used.

Study 3:
To investigate the interaction of Lurasidone with MK-801 specifically in the memory consolidation process of acquiring the passive-avoidance response (McGaugh, 1973, McGaugh, 2000), lurasidone was injected intravenously, 10 min after the animals received the foot-shock training and were returned to their home cages. MK-801 was given as described for Study 2. Fifteen animals per dose group were used.

Absorption, Distribution and Excretion
Lurasidone is readily absorbed and rapidly reaches its peak concentration (Cmax) within 1–4 hours. When taken with food, drug exposure doubles, and the time to reach peak concentration is prolonged by 0.5–1.5 hours. This is independent of the fat or caloric content of the food. Bioavailability is 9–19%. Urine (approximately 9%) and feces (approximately 80%) 6173 L 3902 mL/min Following a single dose of radiolabeled lurasidone, approximately 80% and 9% of the dose are excreted in feces and urine, respectively. After oral administration, lurasidone is rapidly absorbed and reaches peak serum concentrations within approximately 1–3 hours. The orally absorbed dose is approximately 9–19% of the administered dose. Steady-state drug concentrations are reached within 7 days.

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Metabolisms/Metabolites
Lurasidone is metabolized by CYP3A4, with its major active metabolite being ID-14283 (accounting for 25% of parental exposure). Its two minor metabolites are ID-14326 and ID-11614, accounting for 3% and 1% of parental exposure, respectively. Its two inactive metabolites are ID-20219 and ID-20220.
Lurasidone has a high binding rate (99.8%) to serum proteins (including albumin and α1-acid glycoprotein). The drug is primarily metabolized via CYP3A4. The main biotransformation pathways include oxidative N-dealkylation, hydroxylation of the norbornene ring, and S-oxidation. Lurasidone is metabolized into two active metabolites (ID-14283 and ID-14326) and two major inactive metabolites (ID-20219 and ID-20220).

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Biological half-life
40 mg dose = 18 hours; 120 mg - 160 mg dose = 29-37 hours

Medication Use During Pregnancy and Lactation ◉ Overview of Medication Use During Lactation
Lurasidone binds to plasma proteins at a rate exceeding 99%, making it unlikely that significant amounts will be excreted into breast milk, thus affecting breastfed infants. Data from a mother-infant pair appear to support the view that the amount of drug excreted into breast milk is small and has no effect on breastfed infants. Until more data are available, alternative medications are recommended, especially when breastfeeding newborns or premature infants.
◉ Effects on Breastfed Infants
A woman with depressive schizoaffective disorder took 40 mg of lurasidone nightly and 50 mg of desvenlafaxine daily after delivery. She exclusively breastfed her infant. During a 39-day follow-up period, the infant's growth and development were good.
Patients taking second-generation antipsychotics while breastfeeding (n = 576) registered in the National Atypical Antipsychotics Pregnancy Registry were compared with a breastfeeding control group (n = 818) who did not take second-generation antipsychotics. Among patients taking second-generation antipsychotics, 60.4% were taking more than one psychotropic medication. A review of pediatric medical records showed no adverse reactions regardless of whether the infant had been exposed to second-generation antipsychotic monotherapy or combination therapy. No cases of women taking lurasidone were reported.
◉ Effects on lactation and breast milk
The increase in serum prolactin caused by lurasidone is usually uncommon, minor, and less pronounced than with risperidone. One woman who experienced elevated serum prolactin levels, breast engorgement, and galactorrhea while taking risperidone experienced symptom improvement after switching to lurasidone; these side effects completely disappeared when the dose of lurasidone was increased from 20 mg to 40 mg daily. For mothers who have established lactation, prolactin levels may not affect their ability to breastfeed.
Patients taking second-generation antipsychotics while breastfeeding (n = 576) registered with the National Atypical Antipsychotic Pregnancy Registry were compared with a control group of breastfeeding patients with a primary diagnosis of major depressive disorder and anxiety disorder (n = 818). The control group of breastfeeding patients typically received selective serotonin reuptake inhibitors (SSRIs) or selective serotonin and norepinephrine reuptake inhibitors (SNRIs) as antidepressants, but did not use second-generation antipsychotics. Among women taking second-generation antipsychotics, 60.4% were also taking more than one psychotropic medication, compared to 24.4% in the control group. 59.3% of women taking second-generation antipsychotics reported breastfeeding, compared to 88.2% in the control group. Three months postpartum, 23% of women taking second-generation antipsychotics were still exclusively breastfeeding, compared to 47% in the control group. The number of women taking lurasidone was not reported. A 14-year-old girl with hallucinogenic schizophrenia, who had previously been treated with aripiprazole with poor results, was subsequently switched to paliperidone. At age 16, she transitioned from paliperidone to lurasidone, at which point her serum prolactin level rose to 4240 mIU/L (normal range 60-400 mIU/L). As the lurasidone dose was gradually increased to a maximum daily dose of 111 mg, prolactin levels continued to rise, and the patient experienced breast engorgement and galactorrhea. Six out of seven serum prolactin measurements were in the range of 4240 to 6140 mIU/L. After discontinuing lurasidone, her serum prolactin levels returned to normal. In an Italian study on lurasidone treatment of schizophrenia, 2.4% of patients experienced hyperprolactinemia and galactorrhea. Toxicity Summary: Indications and Uses: Lurasidone is indicated for the treatment of schizophrenia, as a monotherapy for major depressive episodes associated with bipolar I disorder (bipolar depression), and can also be used in combination with lithium or valproate for the treatment of major depressive episodes associated with bipolar I disorder (bipolar depression). Human Exposure and Toxicity: In placebo-controlled studies, an increased incidence of cerebrovascular adverse events (cerebrovascular accidents and transient ischemic attacks), including deaths, was observed in elderly patients with dementia-related psychosis treated with certain atypical antipsychotics (aripiprazole, olanzapine, risperidone). The manufacturer states that lurasidone is not approved for the treatment of dementia-related psychosis. Neuroleptic malignant syndrome (NMS) has been reported in patients treated with antipsychotics, including lurasidone. NMS is a potentially fatal syndrome requiring immediate discontinuation of the drug and intensive symptomatic treatment. Reports of rash and pruritus are common in patients treated with lurasidone, while reports of angioedema are rare. In patients with schizophrenia treated with lurasidone, adverse reactions occurring at a rate ≥5% and at least twice the frequency of the placebo group included somnolence (including narcolepsy, excessive somnolence, and sedation), akathisia, nausea, Parkinson's syndrome, and agitation. Aakathisia and somnolence appear to be dose-related adverse reactions. The effects of lurasidone on childbirth are unclear. It is currently unknown whether lurasidone and/or its metabolites are excreted into human milk. Serum lurasidone concentrations in elderly patients aged 65–85 years with psychosis were similar to those in younger adults. Elderly patients with dementia-related psychosis treated with lurasidone had an increased risk of death compared to those receiving placebo. The safety and efficacy of lurasidone in children and adolescents have not been established. Animal studies: Oral administration of lurasidone (at doses of 12 and 36 mg/kg/day) to female rats increased the incidence of breast cancer; the lowest dose, 3 mg/kg/day, resulted in plasma drug concentrations (AUC) 0.4 times higher than those in humans receiving the maximum recommended human dose (MRHD). No increased tumor incidence was observed in male rats at the highest tested dose, which resulted in plasma drug concentrations (AUC) 6 times higher than those in humans receiving the MRHD. Lurasidone is excreted into rat milk. Rats administered lurasidone orally for 15 consecutive days (at doses of 1.5, 15, and 150 mg/kg/day, respectively) before mating, during mating, and before day 7 of gestation experienced estrous cycle disturbances. The no-effect dose was 0.1 mg/kg, approximately 0.006 times the maximum recommended human dose (MRHD, 160 mg/day) based on body surface area. Decreased fertility was observed only at the highest dose, and fertility returned to normal 14 days after discontinuation. The dose that did not affect fertility was 15 mg/kg, approximately equal to the maximum recommended human dose (MRHD) based on body surface area. No effect on male rat fertility was observed with lurasidone administered orally for 64 consecutive days before and during mating at doses up to 150 mg/kg/day (equivalent to 9 times the MRHD based on mg/m² body surface area). No mutations or chromosomal aberrations were found in either in vitro or in vivo studies. The drug was negative in the Ames gene mutation assay, the Chinese hamster lung (CHL) cell assay, and the in vivo mouse bone marrow micronucleus assay at doses up to 2000 mg/kg (based on mg/m² body surface area, equivalent to 61 times the maximum recommended daily human dose of 160 mg).
Drug Interactions
Lurasidone is not a CYP1A2 substrate in vitro; therefore, smoking should not alter the pharmacokinetics of this drug.
Concomitant administration of the potent CYP3A4 inducer rifampin (600 mg daily for 8 days) and lurasidone (single 40 mg dose) reduced serum peak concentrations and AUCs of lurasidone by approximately 86% and 80%, respectively. Rifampin should not be taken concurrently with lurasidone.
Concomitant administration of lurasidone (steady-state dose of 40 mg daily) with oral contraceptives containing ethinylestradiol and norgestrel resulted in comparable peak plasma concentrations and AUCs compared to oral contraceptives alone. Sex hormone-binding globulin concentrations were not significantly affected by concomitant administration. Patients taking lurasidone concurrently do not require dose adjustment of oral contraceptives. Concomitant administration of lurasidone (steady-state dose 120 mg daily) with a single 5 mg dose of midazolam (CYP3A4 substrate) increased peak plasma concentrations and AUC values of midazolam by approximately 21% and 44%, respectively. Patients taking lurasidone concurrently do not require dose adjustment of midazolam. For more complete data on drug interactions of lurasidone (11 in total), please visit the HSDB record page. Hepatotoxicity: Liver dysfunction occurs in 1% to 3% of patients taking lurasidone long-term, but the incidence is similar in placebo and control groups. ALT elevations are usually mild and transient, and often resolve spontaneously even without dose adjustment or discontinuation. There are currently no published reports of clinically significant liver injury (with symptoms or jaundice) caused by lurasidone treatment. Likelihood Score: E (Unlikely to be the cause of clinically significant liver injury).

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Use during pregnancy and lactation
◉ Overview of use during lactation
Lurasidone binds to plasma proteins at a rate exceeding 99%, making it unlikely to be excreted in breast milk in an amount sufficient to affect a breastfed infant. Data from a mother-infant pair appear to support low excretion of the drug in breast milk and no effect on the breastfed infant. Until more data are available, alternative medications may be preferred, especially in breastfed newborns or preterm infants.
◉ Effects on breastfed infants
A woman with depressive schizoaffective disorder took 40 mg of lurasidone nightly and 50 mg of desvenlafaxine daily after delivery. She exclusively breastfed her infant. During a 39-day follow-up period, the infant's growth and development were good.
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 not taking second-generation antipsychotics (n = 818). Among patients taking second-generation antipsychotics, 60.4% were taking more than one psychotropic medication concurrently. A review of pediatric medical records showed no adverse reactions regardless of whether the infant had received second-generation antipsychotic monotherapy or combination therapy. The number of women taking lurasidone was not reported.
◉ Effects on Lactation and Breast Milk
Elevated serum prolactin levels after taking lurasidone are generally uncommon and minor, less so than with risperidone. One woman who experienced elevated serum prolactin levels, breast engorgement, and galactorrhea while taking risperidone experienced improvement after switching to lurasidone; these side effects completely disappeared when the lurasidone dose was increased from 20 mg to 40 mg daily. For established lactating mothers, prolactin levels may not affect their ability to breastfeed. This study compared breastfeeding mothers taking second-generation antipsychotics (n = 576) registered with the National Atypical Antipsychotic Pregnancy Registry with a control group of breastfeeding mothers primarily diagnosed with major depressive disorder and anxiety disorder (n = 818). The control group typically received selective serotonin reuptake inhibitors (SSRIs) or selective serotonin and norepinephrine reuptake inhibitors (SNRIs) but not second-generation antipsychotics. Among women taking second-generation antipsychotics, 60.4% were also taking multiple psychotropic medications, compared to 24.4% in the control group. 59.3% of women taking second-generation antipsychotics reported breastfeeding, compared to 88.2% in the control group. At 3 months postpartum, 23% of women taking second-generation antipsychotics were exclusively breastfeeding, compared to 47% in the control group. No reports have been made regarding the number of women taking lurasidone. A 14-year-old girl with hallucinogenic schizophrenia, who had previously been treated with aripiprazole but with poor efficacy, was switched to paliperidone. At age 16, she transitioned from paliperidone to lurasidone, at which point her serum prolactin level rose to 4240 mIU/L (normal range 60-400 mIU/L). As the lurasidone dose was gradually increased to a maximum daily dose of 111 mg, prolactin levels continued to rise, and the patient experienced breast engorgement and galactorrhea. Six out of seven serum prolactin measurements were in the range of 4240 to 6140 mIU/L. After discontinuing lurasidone, her serum prolactin levels returned to normal. An Italian study showed that 2.4% of patients with schizophrenia treated with lurasidone developed hyperprolactinemia and galactorrhea. [LactMed Drug and Lactation Database] ◈ What is lurasidone? Lurasidone is an antipsychotic medication used to treat schizophrenia and bipolar disorder. Its brand name is Latuda®. 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 changing your medication regimen. Your healthcare provider can discuss with you the benefits of treating your condition and the risks of not treating the condition during pregnancy. ◈ I am taking lurasidone. Will taking lurasidone affect my pregnancy? There are currently no human studies confirming that lurasidone affects pregnancy. ◈ Does taking lurasidone increase the risk of miscarriage? Miscarriage can occur in any pregnancy. There are currently no studies confirming that lurasidone increases the risk of miscarriage. ◈ Does taking lurasidone increase the risk of birth defects? There is a 3-5% risk of birth defects in every pregnancy; this is called background risk. Information on the use of lurasidone during pregnancy is limited. In animal studies in rats and rabbits, no increased risk of birth defects was found. In one case report of lurasidone use during pregnancy, the infant was born healthy with no birth defects. A study of 134 women who took lurasidone during pregnancy found no specific pattern of birth defects.
◈ Does taking lurasidone during pregnancy increase the risk of other pregnancy-related problems?
Currently, no studies have shown that taking lurasidone during pregnancy increases the risk of pregnancy-related problems such as preterm birth (delivery before 37 weeks of gestation) or low birth weight (birth weight less than 2500 grams).
◈ I need to take lurasidone throughout my pregnancy. Will it cause symptoms after the baby is born?
The FDA product label states that newborns exposed to antipsychotic drugs in late pregnancy may experience symptoms. These symptoms may include involuntary muscle movements, changes in muscle tone, lethargy, difficulty breathing, and/or feeding difficulties. Not all infants exposed to antipsychotic drugs during pregnancy will experience these symptoms. These symptoms may be temporary and resolve on their own. Symptomatic treatment can be started if necessary. There are currently no reports of these symptoms occurring during lurasidone use during pregnancy. Due to very limited information regarding lurasidone use during pregnancy, it is difficult to determine whether these symptoms will occur. If you are taking lurasidone, inform your healthcare provider before delivery. Monitoring of the infant for symptoms may be necessary.
◈ Will taking lurasidone during pregnancy affect the child's future behavior or learning?
There is currently no research indicating whether taking lurasidone during pregnancy will cause behavioral or learning problems in the child.
◈ Breastfeeding while taking lurasidone:
Information regarding taking lurasidone while breastfeeding is limited. One report shows a woman taking lurasidone while breastfeeding, but no adverse effects were reported on the breastfed infant. The benefits of taking lurasidone may outweigh the potential risks. Your healthcare provider can discuss taking lurasidone with you and the best treatment option for you. Be sure to consult your healthcare provider about all breastfeeding-related questions.
◈ If a man takes lurasidone, will it affect fertility (the ability to impregnate a partner) or increase the risk of birth defects?
No human studies have been conducted to determine whether lurasidone affects fertility or increases the risk of birth defects (above background risk). Generally, exposure to this medication by the father or sperm donor is unlikely to increase the risk of pregnancy. For more information, please see the “Father Exposure” information sheet on the MotherToBaby website: https://mothertobaby.org/fact-sheets/paternal-exposures-pregnancy/.

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[2]. Eur J Pharmacol. 2007 Oct 31;572(2-3):160-70.

[3]. Pharmacol Rep. 2020 Dec;72(6):1685-1694.

Lurasidone hydrochloride is the hydrochloride salt prepared by reacting lurasidone with an equivalent amount of hydrochloric acid. It is an atypical antipsychotic drug used to treat schizophrenia. It has the effects of a dopaminergic antagonist, a serotonergic antagonist, an adrenergic antagonist, and a second-generation antipsychotic. It contains lurasidone (1+). A thiazole derivative, it is also an atypical antipsychotic drug whose mechanism of action includes: dopamine D2 receptor antagonist, serotonin 5-HT2 receptor antagonist, serotonin 5-HT7 receptor antagonist, adrenergic α2A and α2C receptor antagonist, and a partial serotonin 5-HT1A receptor agonist. It is used to treat schizophrenia and bipolar disorder. See also: lurasidone (with active moiety). Drug Indications For the treatment of schizophrenia in adults aged 18 years and older. Treatment of schizophrenia. Lurasidone [(3aR,4S,7R,7aS)-2-[(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazin-1-ylmethyl]cyclohexylmethyl]hexahydro-4,7-methylene-2H-isoindole-1,3-dione hydrochloride; SM-13496] is an azapyrone derivative and a novel antipsychotic candidate drug. This study aimed to investigate the in vitro and in vivo pharmacological properties of lurasidone. Under similar detection conditions, the receptor binding affinity of lurasidone to several antipsychotic drugs was tested using cloned human receptors or membrane fractions prepared from animal tissues. The results showed that lurasidone exhibits strong binding affinity to dopamine D₂, serotonin 2A (5-HT₂A), 5-HT₇, 5-HT₁A, and norepinephrine α₂C receptors. It exhibits weak affinity for norepinephrine α₁, α₂A, and 5-HT₂C receptors, while its affinity for histamine H₁ and muscarinic acetylcholine receptors is negligible. In vitro functional studies have shown that lurasidone acts as an antagonist on D₂ and 5-HT₇ receptors and as a partial agonist on the 5-HT₁A receptor subtype. Lurasidone demonstrates potent antipsychotic activity, such as inhibiting methamphetamine-induced ADHD and apomorphine-induced stereotyped behaviors in rats, similar to other antipsychotic drugs. Furthermore, lurasidone exhibits only mild extrapyramidal side effects in rodent models. In animal models of anxiety and depression, lurasidone treatment was associated with significant improvement. Lurasidone preferentially promotes dopamine metabolism in the frontal cortex (but not the striatum). Lurasidone also exhibits very weak anti-α1-norepinephrine, anticholinergic, and central nervous system depressant effects. These results suggest that lurasidone possesses antipsychotic activity and similar antidepressant or anxiolytic effects, with a potentially lower risk of extrapyramidal and central nervous system depressant side effects. [1]

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Background
This study aimed to investigate the inhibitory effects of two atypical antipsychotic drugs, ilopiperidone and lurasidone, on major human cytochrome P450 (CYP) enzymes in CYP enzymes (ultramicrosomes) expressed in mixed human liver microsomes and cDNA.
Methods
The activities of the following CYP-specific reactions were determined by high performance liquid chromatography (HPLC): caffeine 3-N-demethylation/CYP1A2, diclofenac 4′-hydroxylation/CYP2C9, piperazine N-demethylation/CYP2C19, ibuprofen 1′-hydroxylation/CYP2D6, and testosterone 6β-hydroxylation/CYP3A4. Results
Ilopride inhibited CYP3A4 activity via a non-competitive mechanism (Ki = 0.38 and 0.3 µM). Ilopride inhibited CYP1A2 in liver microsomes and ultrasomes (Ki values of 2.9 µM and 10 µM, respectively) and CYP2D6 via a competitive mechanism (Ki values of 2.9 µM and 10 µM, respectively). Furthermore, ilopride attenuated the activity of CYP1A2 (Ki values of 45 µM and 31 µM in microsomes and ultrasomes, respectively) and CYP2C19 (Ki values of 6.5 µM and 32 µM, respectively) via a mixed mechanism, but had no effect on CYP2C9. Lurasidone exhibits moderate inhibitory activity against CYP1A2 (Ki values of 12.6 and 15.5 µM in microsomes and ultrasomes, respectively), CYP2C9 (Ki values of 18 and 3.5 µM in microsomes and ultrasomes, respectively), with a mixed inhibitory mechanism (Ki values of 18 and 18.4 µM in microsomes and ultrasomes, respectively); it also exhibits competitive inhibition against CYP3A4 (Ki values of 29.4 and 9.1 µM in microsomes and ultrasomes, respectively). Furthermore, lurasidone also competitively inhibits CYP2D6 activity, but the inhibitory effect is weak (Ki values of 37.5 and 85 µM in microsomes and ultrasomes, respectively).
Conclusion
The studied antipsychotic drug showed inhibitory activity against different CYP enzymes. The results suggest that metabolic/pharmacokinetic interactions with ilopiperidone (primarily involving CYP3A4 and CYP2D6) and lurasidone (involving CYP1A2, CYP2C9, or CYP2C19) may occur during combination therapy. [3]

C28H37CLN4O2S

529.14

528.23

C, 63.56; H, 7.05; Cl, 6.70; N, 10.59; O, 6.05; S, 6.06

367514-88-3

Lurasidone; 367514-87-2; Lurasidone metabolite 14326 hydrochloride; Lurasidone-d8 hydrochloride; Lurasidone Metabolite 14283-d8; 2070009-43-5; Lurasidone metabolite 14326; 186204-33-1; Lurasidone Metabolite 14326-d8

11237860

White to off-white solid powder

198-205°C

9℃

4.196

1

6

5

36

804

6

O=C([C@H]([C@H]1CC[C@@H]2C1)[C@H]2C3=O)N3C[C@@H]4CCCC[C@H]4CN(CC5)CCN5C6=NSC7=CC=CC=C76.Cl

NEKCRUIRPWNMLK-SCIYSFAVSA-N

InChI=1S/C28H36N4O2S.ClH/c33-27-24-18-9-10-19(15-18)25(24)28(34)32(27)17-21-6-2-1-5-20(21)16-30-11-13-31(14-12-30)26-22-7-3-4-8-23(22)35-29-26;/h3-4,7-8,18-21,24-25H,1-2,5-6,9-17H2;1H/t18-,19+,20-,21-,24+,25-;/m0./s1

(1S,2R,6S,7R)-4-[[(1R,2R)-2-[[4-(1,2-benzothiazol-3-yl)piperazin-1-yl]methyl]cyclohexyl]methyl]-4-azatricyclo[5.2.1.02,6]decane-3,5-dione;hydrochloride

SM13496; Lurasidone HCl; SM-13496; 367514-88-3; Lurasidone hydrochloride;; UNII-O0P4I5851I; CHEBI:70732; O0P4I5851I; lurasidone monohydrochloride; HCl, Lurasidone; SM 13496; trade name Latuda

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 (e.g. under nitrogen), avoid exposure to moisture and light.

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: ≥ 0.67 mg/mL (1.27 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 6.7 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: ≥ 0.67 mg/mL (1.27 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 6.7 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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 (Please use freshly prepared in vivo formulations for optimal results.)