Focus on lurasidone: A new atypical antipsychotic for the treatment of schizophrenia

Lurasidone, a new-generation atypical antipsychotic, has been approved by FDA for the treatment of schizophrenia and is under investigation for the treatment of bipolar disorder. This article will discuss the clinical pharmacology, clinical trials, adverse events, drug interactions, dosing and administration, and formulary considerations.

Key Points

Abstract

Lurasidone, a new-generation atypical antipsychotic, has been approved by FDA for the treatment of schizophrenia and is under investigation for the treatment of bipolar disorder. In 4 separate clinical trials, lurasidone has demonstrated efficacy in treating schizophrenia, with total Positive and Negative Syndrome Scale scores decreasing by a range of 14 to 17 points depending on the lurasidone dosage. In addition to the studies in schizophrenia, ongoing trials in patients with bipolar disorder are being completed. The most common adverse events associated with lurasidone treatment are nausea, vomiting, akathisia, dizziness, and sedation. Lurasidone has similar affinity for the dopamine D2 and serotonin 5-HT2A receptors, but a much greater affinity for 5-HT7, 5-HT1A, and a2C-adrenergic subtype receptors, than other atypical antipsychotics. Experimental data support the theory that antagonism of 5-HT7 can improve cognition, memory, and mood symptoms. This may provide a unique place for lurasidone in the treatment of schizophrenia and bipolar disorder. (Formulary. 2010;45:313–317.)

Schizophrenia, a chronic psychiatric disorder affecting approximately 1% of the US population, is characterized by positive (eg, hallucination, delusions), negative (eg, alogia, anhedonia), and cognitive symptoms.1 Second-generation antipsychotics (SGAs) have been the first-line treatment choice for several years, although recent studies have shown that first-generation antipsychotics (FGAs) may be as effective as SGAs when using the primary end point of time to medication discontinuation.2,3 Now, a few of the more effective SGAs-clozapine and olanzapine-have been relegated to second or third line because of risk of metabolic dysfunction, and for clozapine, bone marrow toxicity.4–6 Better tolerated treatments are needed for schizophrenia, as well as ones that are more effective in treating negative symptoms and cognitive impairment.7–9

CHEMISTRY AND PHARMACOLOGY

Lurasidone hydrochloride (SM-13496) is a white to light yellow crystalline powder that is stable for 36 months. It has a molecular formula of C28H36N4O2S ∙ HCl, thus having a molecular weight of 529.14. Lurasidone is sparingly soluble in methanol, slightly soluble in ethanol, and very slightly soluble in acetone and water.10

Similar to many of the other atypical antipsychotics, lurasidone has a high affinity for the dopamine (D)2 and serotonin (5-HT)2A receptors.11 These receptors are theorized to be integral to the antipsychotic effect of these medications. Lurasidone has a much higher selectivity for the D2 receptor than for the D1 or D3 receptors.

Lurasidone has the highest affinity of any atypical antipsychotic for the 5-HT7 receptor. Portions of the brain with a large distribution of 5-HT7 receptors include the thalamic and hypothalamic areas, which are integral to sleep cycles, and the hippocampus, raphe nuclei, and cortical area, which play a role in mood regulation.12 Also, blockade of 5-HT7 in the thalamus, which is an area that aids in sensory functioning, could potentially add to the antipsychotic effect.13 Experimental data support the theory that antagonism of 5-HT7 can improve cognition, memory, and mood symptoms.14,15

In addition to 5-HT7, lurasidone has a much greater affinity for 5-HT1A and a2C-adrenergic subtypes than most atypical antipsychotics.16 Antagonism at these receptors is implicated in improving cognition, negative symptoms, and mood symptoms, such as depression and anxiety.10

The affinity of lurasidone is very low at the a1-adrenergic receptor, which indicates that lurasidone should have a low risk for orthostatic hypotension and sedation.10,16 The affinity at the histamine H1 and muscarinic M1 receptors is virtually nonexistent, which also helps demonstrate a favorable side-effect profile for lurasidone. Histamine antagonists are implicated in causing impaired cognition, sedation, and weight gain, while muscarinic antagonists are known to impair cognition.

PHARMACOKINETICS/PHARMACODYNAMICS

The absorption of lurasidone after oral administration is rapid, with a Tmax of 1.3 hours.10 Absorption is dose-dependent and is also enhanced with food consumption. A single oral dose without food is roughly 20% absorbed, but when taken with food, the AUC increases 3-fold, without any effect on the Tmax. In single-dose studies of <100 mg/d in healthy subjects, the mean terminal half-life ranged from 12.2 to 18.3 hours, but at steady state increased to 36 hours. In single-dose studies of 120 to 160 mg/d in patients with schizophrenia, the mean half-life was much higher at 28.8 to 37.4 hours.

Lurasidone is metabolized primarily though the cytochrome CYP3A4 isoenzyme, with only 0.1% unchanged in the urine.10 Three metabolites are produced and detectable in the serum, but 2 of these are found at extremely low levels (1% and 3%). The primary exo-hydroxy metabolite (ID-14283) is detected in the serum rapidly, with a Tmax of 1.6 to 1.8 hours and a Cmax that is roughly one-fourth (26%) that of lurasidone. ID-14283 is similar pharmacologically to lurasidone, but has a shorter half-life (7.48 to 10 hours).

Although lurasidone is a CYP3A4 substrate, it has not proved to be a significant inhibitor of the CYP450 system. Also, lurasidone and ID-14283 are not substrates for P-glycoprotein. However, high protein binding (99.8%), with affinity for albumin and a-1-glycoprotein, can pose a risk for drug interactions, and special consideration should be taken for certain patient populations, such as the elderly.

The dopamine D2 receptor occupancy was analyzed in a small study using positron-emission tomography scans. Measurements were taken at Tmax after single doses of lurasidone. The study demonstrated a linear increase in occupancy at doses up to 60 mg (~80%), with a slight decrease in occupancy at 80 mg (70%-80%).10

CLINICAL TRIALS

Four 6-week, randomized, double-blind studies have been completed to date comparing lurasidone to placebo (two phase 2, two phase 3).17 Men and women aged 18 to 64 or 75 (depending on the trial) who were hospitalized (until day 7 or 28, depending on clinical trial) for an acute exacerbation of schizophrenia meeting Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria based on the Structured Clinical Interview for DSM-IV Disorders Clinician's Version were enrolled.1,18 Each study had a screening period of 7 to 14 days, with a 3- to 7-day single-blind washout. During the double-blind period, each subject was randomized in a 1:1 ratio to 6 weeks of double-blind, placebo-controlled treatment with a once-daily fixed dose of lurasidone or placebo.

In the first US phase 2 trial (D1050006), subjects were randomly assigned to lurasidone 40 mg (n=50), lurasidone 120 mg (n=49), or placebo (n=50). At study end point, significant differences in mean changes from baseline were demonstrated between placebo, lurasidone 40 mg, and the lurasidone 120-mg groups for the following: Brief Psychiatric Rating Scale (BPRS) total (-4.3, -10.0, -11.3, respectively), Clinical Global Impression Severity (CGI-S) score (0, -0.7, -0.8, respectively), and the Clinical Global Impression Improvement (CGI-I) score (4.0, 3.2, 3.0, respectively). Additionally, the Positive and Negative Syndrome Scale (PANSS) total score was significantly different between lurasidone 120 mg and placebo (-17.4, -5.8, respectively). Response was defined for the study as a decrease in BPRS >20% or CGI-I <2. A responder analysis identified 22.2% of placebo-, 55.3% of 40 mg (P<.002) lurasidone-, and 50.0% of 120 mg (P=.007) lurasidone-treated subjects.10

In the published, second phase 2 trial (D1050196), 90 subjects were randomly assigned to each placebo or lurasidone 80 mg daily. Lurasidone demonstrated significantly greater efficacy on the following: BPRS, last observation carried forward (LOCF) (placebo, -4.2; 80 mg, -8.9; P=.0118); PANSS total score (LOCF) (placebo, -5.5; 80 mg, -14.1; P=.004); PANSS positive score (LOCF) (placebo, -1.7; 80 mg, -4.3; P=.006); negative subscale (LOCF) (placebo, -1.3; 80 mg, -2.9; P=.025); and general psychopathology subscale (LOCF) (placebo, -2.7; 80 mg, -7.0; P=.0061). Additionally, the investigators analyzed the PANSS cognitive score, which is a derived measure of cognition consisting of 5 items from the positive, negative, and general psychopathology scales. Lurasidone 80 mg/d was significantly superior to placebo on this measure as well (80 mg, -2.1; placebo, -0.5; P=.0015). Responder analysis (defined as a >20% improvement in PANSS score) demonstrated significant results for lurasidone compared with placebo (44.4% versus 26.7%, respectively; P=.007).16

PEARL 1 study. An extensive worldwide phase 3 clinical development program has been undertaken by Sunovion Pharmaceuticals to further evaluate the safety and efficacy of lurasidone.19 Preliminary results from the first 2 studies have been presented. The Program to Evaluate the Antipsychotic Response to Lurasidone (PEARL) 1 study randomly assigned 500 patients equally to 4 treatment arms: lurasidone 40 mg/d, 80 mg/d, 120 mg/d, or placebo.

The study demonstrated that the 80-mg/d dose was more effective than placebo at study end point (week 6) on the PANSS total score (P=.011) and CGI-S (P=.005). Both the 80- and 120-mg/d doses were significantly different than placebo in decreasing the PANSS positive score (P<.001, P<.01, respectively). The 40-mg/d group did not separate from placebo at the study end point on these scales. A responder analysis was completed (defined as >30% decrease on the PANSS total score) and identified significant differences versus placebo for the 80- and 120-mg/d groups (placebo 38%, 80 mg 52%, P=.028; 120 mg 50%, P=.058).19

PEARL 2 study. The PEARL 2 study randomly assigned 478 patients to lurasidone 40 mg or 120 mg, olanzapine 15 mg, or placebo once daily.20 Both the 40-mg/d and 120-mg/d lurasidone doses were significantly better than placebo at study end point, week 6, on the PANSS total score (40 mg, P<.001; 120 mg, P<.05) and the CGI-S (40 mg, P<.01; 120 mg, P<.05). Additionally, the lurasidone 40-mg/d and 120-mg/d doses were significantly different than placebo on the positive and negative PANSS subscales (positive: P<.05 for both; negative: 40 mg, P<.01, 120 mg, P<.05).

PEARL 3 study. Recently, Sunovion Pharmaceuticals completed the PEARL 3 trial, an additional 6-week study comparing lurasidone 80 mg/d or 160 mg/d to placebo, with quetiapine XR 600 mg/d as an active comparator in acute schizophrenia. Results have not been published yet.

Extension trial for PEARL 3. An extension trial of PEARL 3 is still recruiting subjects (NCT00789698), in addition to 2 trials evaluating lurasidone for the treatment of schizophrenia or schizoaffective disorder in subjects switched from other antipsychotic agents (NCT01143077, NCT01143090).21

An additional trial (NCT-01173874) investigating cognitive remediation in schizophrenia is planned but has not yet started recruiting: Clinical and Biomarker Assessment of Efficacy of Cognitive Remediation in Patients with Schizophrenia Stabilized on Lurasidone.21

Sunovion Pharmaceuticals is also investigating the use of lurasidone in the treatment of bipolar I depression as monotherapy (NCT00868699, NCT00868959) and as an add-on to lithium or valproic acid (NCT00868452). These 3 trials are all currently recruiting subjects.21

ADVERSE EVENTS

In the phase 2 trials, lurasidone was well tolerated, with an overall low incidence of significant adverse events. The adverse effects with an incidence of >5% (and twice the placebo rate) were nausea (10%-18%), vomiting (0-8.3%), akathisia (6.7%18.3%), dizziness (1%-10%), and sedation (8.9%16%).10,16

Extrapyramidal symptoms (EPS). In an analysis of 5 placebo-controlled phase 2 and 3 studies conducted by Cucchairo et al, the EPS profiles of lurasidone, haloperidol, olanzapine, and placebo were compared.22 EPS was assessed by 3 different scales-Abnormal Involuntary Movements Scale (AIMS), Simpson-Angus Scale (SAS), and Barnes Akathisia Rating Scale (BAS)-in addition to the use of anticholinergic medications. Lurasidone was determined to not be slightly or significantly associated with movement disorders. The mean changes from baseline for the AIMS, SAS, and BAS were, respectively, for lurasidone, +0.1, +0.03, +0.2; for haloperidol, +0.8, +0.12, +0.6; for olanzapine, -0.1, -0.01, 0.0; and for placebo, +0.1, 0.00, 0.0. Patients treated with lurasidone had an increased need for anticholinergic medications as dosage increased from 40 mg (18%) to 120 mg (32%). Across the analysis, 23% of the lurasidone group (n=1,004) required anticholinergic medications, which was more than that required for both placebo (11%) and olanzapine (18%), but less than for haloperidol (53%).

Metabolic syndrome symptoms. PEARL 2 examined the short-term metabolic adverse effects of lurasidone. The number of subjects with significant weight gain (>7% change in weight) was less with lurasidone than with placebo and olanzapine (5.9%, 6.9%, 34.4%, respectively).20 The median changes in glucose and insulin associated with lurasidone both decreased (-1.0 mg/dL and -0.55 mU/L, respectively), for olanzapine increased (median changes of +4.0 mg/dL and +1.50 mU/L), and for placebo remained essentially unchanged (+1.0 mg/dL and -0.10 mU/L). Lurasidone also decreased cholesterol levels with a median change of -7.0, -5.0, and 0.0 mg/dL for total cholesterol, low-density lipoprotein cholesterol (LDL), and high-density lipoprotein cholesterol (HDL), compared to placebo with median changes of -5.0, -4.0, and -1.0 mg/dL, and olanzapine +9.0, +7.0, and -2.0 mg/dL. In addition to cholesterol, triglyceride levels favored lurasidone, with a mean increase of +1.0 mg/dL, significantly less than the +24.0 mg/dL increase seen with olanzapine. (Placebo demonstrated a -1.0 mg/dL decrease.)23

The effect on waist circumference, body mass index (BMI), and weight also was compared. Lurasidone caused a slight increase in weight and BMI, but olanzapine caused a more significant increase in all 3 categories. The median weight, BMI, and waist circumference changes were as follows: lurasidone +0.7 kg, 0.2 kg/m2 , 0.0 cm; olanzapine +3.1 kg, +1.1 kg/m2 , +2.0 cm; and placebo 0.0 kg, 0.0 kg/m2 , 0.0 cm.23 In the study by Nakamura et al, there was no significant difference between lurasidone and placebo in total cholesterol, HDL, LDL, triglyceride, or blood glucose levels.16 Overall, the effects of lurasidone on increasing the risk of developing metabolic syndrome is minimal.

Hyperprolactinemia.Lurasidone has shown evidence of increasing prolactin levels, which is dose dependent and slightly greater in women than men. The mean change in prolactin levels from baseline in the analysis of 5 placebo-controlled phase 2 and 3 studies conducted by Cucchairo et al was found to be +1.1 ng/mL as lurasidone dose was increased from 40 mg (+0.3 mg/dL) to 120 mg (+3.4 mg/dL).22 This was compared to mean changes in prolactin with haloperidol +8.5 ng/mL, olanzapine +3.7 ng/mL, and placebo -0.5 ng/mL. In the Nakamura et al study, the prolactin increase was statistically significant compared with placebo (+2.4 ng/mL vs. -0.3 ng/mL; P< 0.05). However, in this study the patients did not experience any adverse events related to this increase in prolactin levels.16

Electrocardiographic changes. There was no significant increase in the QTc >500 msec with lurasidone treatment. Lurasidone, haloperidol, olanzapine, and placebo were compared, with the following results in msec: +1.5 (n=972), -2.8 (n=67), +4.1 (n=121), +1.9 (n=436).22 Treatment with lurasidone has not been shown to be associated with ECG abnormalities. In Nakamura et al, none of the participants experienced increases >500 msec.16

DRUG INTERACTIONS

Lurasidone is metabolized through the CYP system mainly through 3A4, providing opportunities for drug-drug interactions. Ketoconazole, a well-known 3A4 inhibitor increased the area under the curve (AUC) of lurasidone 9.3 times as well as the Cmax 6.8-fold when given to healthy volunteers at 400 mg/d for 7 days. Another inhibitor to the 3A4 system, diltiazem was also investigated in conjunction with lurasidone, yielding an increased AUC and Cmax in lurasidone levels and a 2-fold increase in ID-14283 (lurasidone metabolite). Diltiazem was given at a dose of 240 mg/d for 7 days in healthy volunteers. Lastly, the oral contraceptive Ortho Tri-Cyclen was given for a 28-day cycle, and no increase in serum levels was evident indicating there is no drug-drug interaction between the two.10

Lurasidone has not been shown to affect protein binding of the few drugs already studied, although it is 99.8% protein bound. Lurasidone is not a P-glycoprotein substrate, but results are pending in a study evaluating interactions with digoxin, since some studies show it may have an effect on digoxin transport. Co-administration of lurasidone and rifampin has resulted in decease in lurasidone AUC and Cmax of 85%. Lurasidone dosed at 120 mg at steady state demonstrates weak CYP3A inhibition, resulting in a marginal increase in midazolam exposure, and there has been no demonstration of an interaction with lithium.10, 24

DOSING AND ADMINISTRATION

The safety and efficacy of lurasidone has been evaluated across a dosing range from 20 mg/d to 120 mg/d. The 20-mg dose was proven to be less effective in terms of improvement in schizophrenia symptoms than higher doses. When safety and side effect profiles were compared across the dosage range, all doses in the range of 20 mg/d to 120 mg/d were well tolerated, yet there were lower discontinuation rates due to adverse events with the lower doses. In conclusion, it was found that 40 mg/d was considered optimal in the outpatient population, and 80 mg/d was more effective in the inpatient population.

FORMULARY CONSIDERATIONS

For the past several years, the SGAs have been the first-line choice for the treatment of schizophrenia. Recent studies have shown that the FGAs may be as effective as SGAs when the primary end point is time to discontinuation of medication. Although FGAs and current SGAs are effective for the positive symptoms of schizophrenia, more effective treatment strategies are needed for the negative symptoms and cognitive impairment associated with schizophrenia.

Lurasidone is a new-generation atypical antipsychotic that was recently approved by FDA for the treatment of schizophrenia and is under investigation for the treatment of bipolar disorder.

The efficacy data for lurasidone have been evaluated for dosages 20 mg to 120 mg per day. The 20-mg/d dose is less effective in terms of improvement in schizophrenia symptoms compared with higher doses. The 40-mg/d dose has been considered optimal in the outpatient population, and the 80-mg/d dose is more effective in the inpatient population.

The most common adverse events associated with lurasidone treatment are nausea, vomiting, akathisia, dizziness, and sedation. With the propensity of several atypical antipsychotics to cause metabolic disturbances or metabolic syndrome, new medications are needed that minimize this risk. Clinical trials of lurasidone have demonstrated that there are minimal risks for the development of metabolic syndrome. Additionally, there are no significant increases in QTc and only minimal increases in prolactin levels, which are dose dependent.

In addition to lurasidone's affinity for the D2 and 5-HT2A receptors, it has the highest affinity of any atypical antipsychotic for the 5-HT7 receptor. Experimental data support the theory that antagonism of 5-HT7 can improve cognition, memory, and mood symptoms. Additionally, lurasidone has a much greater affinity for 5-HT1A and a2-adrenergic receptors, which have been implicated in improving cognition, negative symptoms, and mood symptoms, such as depression and anxiety.

In summary, clinicians will need to consider lurasidone's favorable metabolic profile, low incidence of EPS, and potential risk of nausea, vomiting, sedation, and dizziness when making a formulary decision. The receptor binding profile may provide lurasidone with a unique place in the treatment of schizophrenia and bipolar disorder, although more, longer-term studies are needed to further explore these ideas.

Dr Ehret is an assistant professor, University of Connecticut, Storrs.
Dr Sopko is an assistant professor, Touro College, New York, N.Y.
Ms Lemieux is a student at the University of Connecticut, Storrs.

Disclosure Information: The authors report no financial disclosures as related to products discussed in this article.

In each issue, the "Focus on" feature reviews a newly approved or investigational drug of interest to pharmacy and therapeutics committee members. The column is coordinated by Robert A. Quercia, MS, RPh, medical editor, University of Connecticut/Hartford Hospital, Evidence-based Practice Center, Hartford, Conn., and adjunct associate professor, University of Connecticut School of Pharmacy, Storrs, Conn; and by Craig I. Coleman, PharmD, associate professor of pharmacy practice, University of Connecticut School of Pharmacy, and director, Pharmacoeconomics and Outcomes Studies Group, Hartford Hospital.

EDITORS' NOTE: The clinical information provided in "Focus on" articles is as current as possible. Due to regularly emerging data on developmental or newly approved drug therapies, articles include information published or presented and available to the author up until the time of the manuscript submission.

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