5-HT2A ( Ki = 0.5 nM ); 5-HT7 receptor ( Ki = 0.5 nM ); D2 receptor ( Ki = 1 nM ); 5-HT1A receptor ( Ki = 6.4 nM )

Lurasidone (SM-13496) exhibits an antagonistic effect on dopamine D2 and 5-HT7, with IC50 values of 1.68±0.09 and 0.495±0.090 nM, respectively. Additionally, luerazidone (SM-13496) has an IC50 of 6.75±0.97 nM, making it a partial agonist of the 5-HT1A receptor. Lurasidone (SM-13496) exhibits a higher affinity for dopamine D2 and 5-HT2A receptors than other tested antipsychotics, according to in vitro receptor binding experiments. Lurasidone (SM-13496) has a KB value of 2.8±1.1 nM[1], which indicates that it opposes dopamine-stimulated [35S]GTPηS binding in a concentration-dependent manner. However, it does not increase [35S]GTPηS binding to the membrane preparations for dopamine D2 receptors on its own.

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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].

In the frontal cortex and striatum, luerazidone (SM-13496) dose-dependently raises the ratio of DOPAC/dopamine; however, it preferentially affects the frontal cortex over the striatum, particularly at higher doses. Comparable in potency to olanzapine (ED50 values 1.1 to 5.1 mg/kg), clozapine (ED50 values 9.5 to 290 mg/kg), and haloperidol (ED50 values 0.44 to 1.7 mg/kg), lurasidone (SM-13496) (ED50 values 2.3 to 5.0 mg/kg) exhibits a slightly lower potency. The ED50 values of lueradone (SM-13496) are 6.3 mg/kg, and it inhibits the conditioned avoidance response (CAR) in rats in a dose-dependent manner at 1 to 10 mg/kg. Lurasidone (SM-13496), with ED50 values of 5.6 and 3.0 mg/kg, respectively, dose-dependently inhibits p-chloroamphetamine (p-CAMP)-induced hyperthermia and tryptamine (TRY)-induced forepaw clonic seizures. Rats receive more shocks in the conflict test when given luerasidone (SM-13496) at doses ranging from 0.3 to 30 mg/kg (p<0.01), which is dose-dependent and statistically significant[1].

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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. Lurasidone (SM-13496) is given 1, 2, 4, and 8 hours prior to the MAP injection in order to test the effect's persistence. 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

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 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 death, 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. Neuropressor Malignant Syndrome (NMS): This is a potentially fatal syndrome requiring immediate discontinuation of the drug and intensive symptomatic treatment. This syndrome has been reported in patients taking antipsychotics (including lurasidone). Reports of rash and pruritus are common in patients taking lurasidone, while reports of angioedema are rare. In patients receiving lurasidone for schizophrenia, adverse reactions occurring at a rate ≥5% and at least twice the rate in the placebo group included somnolence (including narcolepsy, 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 unknown. It is currently unknown whether lurasidone and/or its metabolites are excreted into human breast milk. In elderly patients aged 65–85 years with psychosis, serum lurasidone concentrations were similar to those in younger adults. Elderly patients with dementia-related psychosis receiving lurasidone had an increased risk of death compared to the placebo group. The safety and efficacy of lurasidone in children and adolescents have not been established. Animal studies: In female rats, oral administration of lurasidone at 12 and 36 mg/kg/day increased the incidence of breast cancer: the lowest dose of 3 mg/kg/day produced plasma concentrations (AUC) 0.4 times that of humans receiving the maximum recommended human dose (MRHD). In male rats, no tumor growth was observed up to the highest tested dose, which produced plasma concentrations (AUC) six times higher than those in humans receiving the maximum recommended human dose (MRHD). Lurasidone is distributed into the milk of rats. Oral administration of lurasidone to rats for 15 consecutive days before mating, during mating, and before day 7 of gestation resulted in estrous cycle disturbances. The no-effect dose was 0.1 mg/kg, approximately 0.006 times the MRHD (maximum recommended human dose) of 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 no-effect dose leading to decreased fertility was 15 mg/kg, approximately the MRHD based on body surface area. In male rats, oral administration of lurasidone for 64 consecutive days before and during mating at doses up to 150 mg/kg/day (9 times the MRHD based on mg/m² body surface area) did not affect fertility. The drug did not induce mutations or chromosomal aberrations in in vitro or in vivo studies. In the Ames gene mutation assay, Chinese hamster lung (CHL) cell assay, and in vivo mouse bone marrow micronucleus assay, results were negative at doses up to 2000 mg/kg (equivalent to 61 times the maximum recommended human daily dose of 160 mg based on mg/m² body surface area). Interactions Lurasidone is not a substrate for CYP1A2 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 (40 mg single dose) reduced serum peak lurasidone concentration and AUC by approximately 86% and 80%, respectively. Rifampin should not be taken concurrently with lurasidone.
When lurasidone (steady-state dose 40 mg daily) is taken concurrently with oral contraceptives containing ethinylestradiol and norgestrel, the peak plasma concentrations and AUC values of ethinylestradiol and norgestrel are comparable compared to oral contraceptives taken alone. Sex hormone-binding globulin concentrations are also not significantly affected by concurrent administration. Patients taking lurasidone concurrently do not need to adjust their oral contraceptive dosage.
When lurasidone (steady-state dose 120 mg daily) is taken concurrently with a single 5 mg dose of midazolam (CYP3A4 substrate), the peak plasma concentration and AUC value of midazolam may increase by approximately 21% and 44%, respectively. Patients taking lurasidone concurrently do not need to adjust their midazolam dosage.
For more complete data on drug interactions of lurasidone (out of 11), please visit the HSDB record page.

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Hepatotoxicity
Liver function abnormalities occur in 1% to 3% of patients taking lurasidone long-term, but the incidence is similar in placebo and control patients. Elevations in ALT 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. Probability 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 breastfed infants. Data from a mother-infant pair appear to support low excretion of the drug in breast milk and no effect on breastfed infants. 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 postpartum. 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 Antipsychotic Pregnancy Registry were compared with a breastfeeding control group (n = 818) not taking second-generation antipsychotics. Among patients taking second-generation antipsychotics, 60.4% were concurrently taking more than one psychotropic medication. A review of pediatric 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 are generally uncommon and less pronounced 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 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 lactating patients on second-generation antipsychotics registered with the National Atypical Antipsychotic Pregnancy Registry (n = 576) with a control group of lactating patients with a primary diagnosis of major depressive disorder and anxiety disorder (n = 818). The control group of lactating patients typically received selective serotonin reuptake inhibitors (SSRIs) or selective serotonin and norepinephrine reuptake inhibitors (SNRIs) but did not use second-generation antipsychotics. Among women taking second-generation antipsychotics, 60.4% were also taking multiple antipsychotics, 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 were found regarding the number of women taking lurasidone. A 14-year-old girl with hallucinogenic schizophrenia, initially 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 tests showed results ranging from 4240 to 6140 mIU/L. Her serum prolactin levels returned to normal after discontinuing lurasidone.
An Italian study showed that 2.4% of patients treated with lurasidone for schizophrenia experienced hyperprolactinemia and galactorrhea.

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Drugs & Lactation Database (LactMed)
◈ 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 take lurasidone. Will taking lurasidone affect 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, known as background risk. Information on lurasidone use 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?
There are currently no studies suggesting 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 in my baby after birth?
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 in pregnancy. Information on lurasidone use during pregnancy is very limited, making it difficult to determine whether these symptoms will occur. If you are taking lurasidone, inform your healthcare provider before delivery. Symptom monitoring of the infant may be necessary.
◈ Will taking lurasidone during pregnancy affect my child's future behavior or learning?
There is currently no research indicating whether taking lurasidone during pregnancy will cause behavioral or learning problems in children.
◈ Breastfeeding while taking lurasidone:
Information regarding the use of lurasidone while breastfeeding is limited. One report shows a woman taking lurasidone while breastfeeding. No adverse reactions were observed in the breastfed infant. The benefits of taking lurasidone likely outweigh the potential risks. Your healthcare provider can discuss the use of lurasidone with you and the treatment option best suited to you. Be sure to consult your healthcare provider about all your questions regarding breastfeeding.
◈ Does taking lurasidone 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 the drug by the father or sperm donor is unlikely to increase the risk of pregnancy. For more information, see the “Paternal Exposure to Drugs” information sheet on the MotherToBaby website: https://mothertobaby.org/fact-sheets/paternal-exposures-pregnancy/.

[1]. Pharmacological profile of lurasidone, a novel antipsychotic agent with potent 5-hydroxytryptamine 7 (5-HT7) and 5-HT1A receptor activity. J Pharmacol Exp Ther. 2010 Jul;334(1):171-81.

[2]. Lurasidone (SM-13496), a novel atypical antipsychotic drug, reverses MK-801-induced impairment of learning and memory in the rat passive-avoidance test. Eur J Pharmacol. 2007 Oct 31;572(2-3):160-70.

[3]. The atypical neuroleptics iloperidone and lurasidone inhibit human cytochrome P450 enzymes in vitro. Evaluation of potential metabolic interactions. Pharmacol Rep. 2020 Dec;72(6):1685-1694.

[4]. Development of a validated high-performance liquid chromatographic method for the determination of Lurasidone in pharmaceuticals. Marmara Pharm J. 2017;21 (4): 931-937.

Lurasidone is an N-arylpiperazine compound with the chemical name (3aR,4S,7R,7aS)-2-{[(1R,2R)-2-(piperazin-1-ylmethyl)cyclohexyl]methyl}hexahydro-1H-4,7-methyleneisoindole-1,3(2H)-dione, wherein the N4 position of the piperazine ring is substituted with a 1,2-benzothiazol-3-yl group. Lurasidone (usually in hydrochloride form) is used as an atypical antipsychotic for the treatment of schizophrenia. It has the effects of an adrenergic antagonist, dopaminergic antagonist, serotonergic antagonist, and second-generation antipsychotic. It is a 1,2-benzoisothiazolium compound, an N-arylpiperazine compound, a bridging compound, and a dicarboxyimide compound. It is functionally related to maleimide. It is the conjugate base of lurasidone (1+). Lurasidone is an atypical antipsychotic developed by Sumitomo Pharmaceuticals, Ltd. of Dai Nippon. It was approved by the U.S. Food and Drug Administration (FDA) on October 29, 2010, for the treatment of schizophrenia and is currently awaiting U.S. approval for the treatment of bipolar disorder. Lurasidone is an atypical antipsychotic. Lurasidone is a second-generation (atypical) antipsychotic used to treat schizophrenia and bipolar depression. The incidence of elevated serum transaminases during lurasidone treatment is low, but no clinically significant cases of acute liver injury have been found. It is a thiazole derivative, an atypical antipsychotic whose mechanism of action is as a dopamine D2 receptor antagonist; a serotonin type 2 receptor antagonist, a serotonin type 7 receptor antagonist, an adrenergic α2A and α2C receptor antagonist, and a partial serotonin type 1A receptor agonist. It is used to treat schizophrenia and bipolar disorder. See also: Lurasidone hydrochloride (in salt form). Drug Indications Lurasidone is indicated for the treatment of schizophrenia in patients aged 13 years and older. It may also be used as monotherapy for bipolar depression in patients aged 10 years and older, or in combination with lithium or valproate for the treatment of bipolar depression in adults. For the treatment of schizophrenia in adults aged 18 years and older. Mechanism of Action Lurasidone is an atypical antipsychotic that improves cognitive function by antagonizing D2 and 5-HT2A receptors (mixed serotonin and dopamine activity). Antagonism of serotonin receptors is thought to improve negative symptoms of psychosis and reduce extrapyramidal side effects typically associated with typical antipsychotics. Lurasidone is a benzisothiazol derivative antipsychotic, also known as an atypical or second-generation antipsychotic. Lurasidone is also described as an azaspirone derivative. Although the exact mechanism of action of lurasidone and other antipsychotic drugs in treating schizophrenia is not fully understood, studies suggest that lurasidone's efficacy is achieved through the combined antagonism of central dopamine type 2 (D2) and serotonin type 2 (5-HT2A) receptors. Lurasidone is an antagonist with high affinity for D2, 5-HT2A, and 5-HT7 receptors in vitro, and moderate affinity for α2C adrenergic receptors. In vitro, it exhibits partial agonist activity against 5-HT1A receptors and antagonist activity against α2A adrenergic receptors. Lurasidone has a weak affinity for α1-adrenergic receptors and very low or no affinity for histamine (H1) and muscarinic (M1) receptors.

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Therapeutic Use
Lurasidone (Latuda) is indicated for the treatment of patients with schizophrenia.
/US Product Label Includes/
Lurasidone (Latuda) can be used as monotherapy for the treatment of patients with major depressive episodes of bipolar I disorder (bipolar depression). /US Product Label Includes/
Lurasidone (Latuda) can be used in combination with lithium or valproate as adjunctive therapy for the treatment of patients with major depressive episodes of bipolar I disorder (bipolar depression). /US Product Label Includes/
The efficacy of lurasidone (Latuda) in treating manic bipolar disorder has not been established.
The efficacy of long-term use of lurasidone (Latuda) (i.e., longer than 6 weeks) has not been confirmed in controlled studies.Therefore, physicians choosing long-term use of Latuda should periodically reassess the long-term efficacy of the drug for patients.

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Drug Warning
/Black Box Warning/ Warning: Increased mortality in patients with dementia-related psychosis; and suicidal ideation and behavior. Patients with dementia-related psychosis receiving antipsychotic medication have an increased risk of death. Latuda is not approved for the treatment of dementia-related psychosis. Short-term studies have shown that antidepressants increase the risk of suicidal ideation and behavior in children, adolescents, and young adults. These studies did not show an increased risk of suicidal ideation and behavior in patients over 24 years of age; however, the risk was reduced in patients 65 years of age and older. Patients of all ages starting antidepressant treatment should be closely monitored for worsening of their condition and for the occurrence of suicidal ideation and behavior. Family members and caregivers should be informed of the need for close monitoring of the patient's condition and communication with the prescribing physician.
Contraindications: Known hypersensitivity to lurasidone hydrochloride or any component of its preparations. Angioedema has been reported. Concomitant use of potent cytochrome P-450 (CYP) isoenzyme 3A4 (CYP3A4) inhibitors (e.g., ketoconazole) or potent CYP3A4 inducers (e.g., rifampin).
The risk of death appears to be increased in older patients with dementia-related psychosis receiving antipsychotic treatment. An analysis of 17 placebo-controlled trials (mean duration 10 weeks) showed that mortality rates in older patients treated with atypical antipsychotics (e.g., aripiprazole, olanzapine, quetiapine, risperidone) were approximately 1.6 to 1.7 times higher than in the placebo group. In typical 10-week controlled trials, mortality rates were approximately 4.5% in the drug treatment group and approximately 2.6% in the placebo group. Although the causes of death varied, most deaths appeared to be related to cardiovascular diseases (e.g., heart failure, sudden death) or infectious diseases (e.g., pneumonia). Observational studies have shown that, similar to atypical antipsychotics, treatment with conventional (first-generation) antipsychotics may also increase mortality; the extent to which the increased mortality observed in observational studies is attributable to the antipsychotics themselves, rather than certain patient characteristics, is currently unclear. The manufacturer states that lurasidone is not approved for the treatment of dementia-related psychosis.
In placebo-controlled studies, an increased incidence of adverse cerebrovascular events (cerebrovascular accidents and transient ischemic attacks), including death, was observed in elderly patients with dementia-related psychosis treated with certain atypical antipsychotics (aripiperazole, olanzapine, risperidone). The manufacturer states that lurasidone is not approved for the treatment of dementia-related psychosis.
For more complete data on drug warnings for lurasidone (27 in total), please visit the HSDB record page.
Pharmacodynamics
Lurasidone is a benzothiazole derivative and an antagonist that binds with high affinity to dopamine-2 (D2) receptors (Ki = 0.994 nM), 5-HT2A (Ki = 0.47 nM) receptors, and 5-HT7 receptors (Ki = 0.495 nM). It also binds with moderate affinity to α-2C adrenergic receptors (Ki = 10.8 nM) and is a partial agonist of 5-HT1A receptors (Ki = 6.38 nM). Its effects on histaminergic and muscarinic receptors are negligible. Lurasidone hydrochloride is the hydrochloride salt prepared by reacting lurasidone with an equivalent amount of hydrochloric acid. It is an atypical antipsychotic used to treat schizophrenia. It has dopaminergic, serotonergic, adrenergic, and second-generation antipsychotic effects. It contains lurasidone (1+). A thiazole derivative, also an atypical antipsychotic, its mechanism of action is as a dopamine D2 receptor antagonist. Serotonin 5-HT2 receptor antagonists, serotonin 5-HT7 receptor antagonists, adrenergic α2A and α2C receptor antagonists, and some serotonin 5-HT1A receptor agonists. It is used to treat schizophrenia and bipolar disorder.
See also: Lurasidone (with the active moiety).

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Drug Indications
For the treatment of schizophrenia in adults aged 18 years and older.
Treatment of schizophrenia.

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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. This study aimed to investigate the in vitro and in vivo pharmacological properties of lurasidone. Under similar testing 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 exhibited strong binding affinity to dopamine D₂, serotonin 2A (5-HT₂A), 5-HT₇, 5-HT₁A, and norepinephrine α₂C receptors. Its affinity for norepinephrine α₁, α₂A, and 5-HT₂C receptors was weaker, while its affinity for histamine H₁ and muscarinic acetylcholine receptors was negligible. In vitro functional experiments indicated that lurasidone acts as an antagonist on D₂ and 5-HT₇ receptors and as a partial agonist on the 5-HT₁A receptor subtype. Lurasidone exhibits potent antipsychotic activity, such as inhibiting methamphetamine-induced hyperactivity and apomorphine-induced stereotyped behavior in rats, similar to other antipsychotics. In addition, lurasidone has only mild extrapyramidal side effects in rodent models. In animal models of anxiety and depression, lurasidone treatment was associated with significant improvement. Lurasidone has a preferential effect on promoting dopamine metabolism in the frontal cortex (but not the striatum). The anti-α1-norepinephrine, anticholinergic and central nervous system depressant effects of lurasidone are also very weak. These results suggest that lurasidone has antipsychotic activity and similar antidepressant or anti-anxiety effects with a potentially low 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 antipsychotics, ilopiperidone and lurasidone, on the major human cytochrome P450 (CYP) enzyme in CYP enzymes expressed in mixed human liver microsomes and cDNA (ultramicrosomes).
Methods
High-performance liquid chromatography (HPLC) was used to determine the activities of the following CYP-specific reactions: caffeine 3-N-demethylation/CYP1A2, diclofenac 4′-hydroxylation/CYP2C9, piperazine N-demethylation/CYP2C19, ibuprofen 1′-hydroxylation/CYP2D6, and testosterone 6β-hydroxylation/CYP3A4.
Results
Iloperone inhibited the activity of CYP3A4 via a non-competitive mechanism (Ki = 0.38 and 0.3 µM). Iloperone inhibited CYP1A2 in liver microsomes and ultrasomes (Ki values of 2.9 µM and 10 µM, respectively), and inhibited CYP2D6 via a competitive mechanism (Ki values of 2.9 µM and 10 µM, respectively). Furthermore, ilopiperidone attenuates 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 in microsomes and ultrasomes, respectively) through a mixed mechanism, but has 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), and CYP2C19 through a mixed 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). In addition, lurasidone also competitively inhibits CYP2D6 activity, but the inhibition is weak (Ki values in microsomes and ultrafine particles are 37.5 and 85 µM, respectively).
Conclusion
The antipsychotic drugs studied showed inhibitory effects on different CYP enzymes. The results indicate that metabolic/pharmacokinetic interactions with ilopiperidone (mainly involving CYP3A4 and CYP2D6) and with lurasidone (involving CYP1A2, CYP2C9, or CYP2C19) may occur during combination therapy. [3]

C28H36N4O2S

492.682

492.255

C, 68.26; H, 7.37; N, 11.37; O, 6.49; S, 6.51

367514-87-2

Lurasidone Hydrochloride; 367514-88-3; Lurasidone metabolite 14326 hydrochloride; Lurasidone-d8; 1132654-54-6; Lurasidone-d8 hydrochloride; Lurasidone metabolite 14326; 186204-33-1

213046

White to off-white solid powder

1.3±0.1 g/cm3

623.4±55.0 °C at 760 mmHg

330.8±31.5 °C

0.0±1.8 mmHg at 25°C

1.637

4.52

0

6

5

35

804

6

O=C([C@H]1[C@H]2C[C@H](CC2)[C@@H]31)N(C[C@H](CCCC4)[C@@H]4CN5CCN(CC5)C6=NSC7=CC=CC=C67)C3=O

PQXKDMSYBGKCJA-CVTJIBDQSA-N

InChI=1S/C28H36N4O2S/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/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

trade name Latuda; SM 13496; Lurasidone; 367514-87-2; lurasidona; (3aR,4S,7R,7aS)-2-((1R,2R)-2-(4-(1,2-Benzothiazol-3-yl)piperazin-1-ylmethyl)cyclohexylmethyl)hexahydro-4,7-methano-2H-isoindole-1,3-dione; lurasidonum; UNII-22IC88528T; CHEBI:70735; HSDB 8228; SM-13496; SM13496

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: (1). This product requires protection from light (avoid light exposure) during transportation and storage.  (2). This product is not stable in solution, please use freshly prepared working solution for optimal results.

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

DMSO: 7~20.83 mg/mL (14.2~42.3 mM)
Ethanol: ~3.3 mg/mL (~6.8 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (4.22 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 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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