Lurasidone hydrochloride is considered an atypical or second-generation antipsychotic agent.1,2,9
Lurasidone hydrochloride is used for the treatment of schizophrenia in adults and adolescents 13-17 years of age.1,2,5,88,98,100,101
Efficacy of lurasidone in the management of schizophrenia in adults was established in 5 placebo-controlled, fixed-dose clinical trials of 6 weeks' duration in patients who met Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV criteria for schizophrenia.1,2,5,88,100,101 Two of these studies included an active-control arm (olanzapine or extended-release quetiapine) to assess assay sensitivity.1,88 The studies used either the Positive and Negative Syndrome Scale (PANSS) or the Brief Psychiatric Rating Scale derived (BPRSd) and the Clinical Global Impression severity scale (CGI-S) to assess the effects of drug treatment in improving clinical manifestations of schizophrenia.1,2,5,88,100,101 Studies 1 and 3 both evaluated 2 fixed dosages of lurasidone hydrochloride (40 or 120 mg daily), study 2 evaluated a fixed dosage of 80 mg daily, study 4 evaluated 3 fixed dosages (40, 80, or 120 mg daily), and study 5 evaluated 2 fixed dosages of the drug (80 or 160 mg daily).1,2,5,88,100,101 In all 5 studies, lurasidone was found to be more effective than placebo;1,2,5,88,100,101 however, in study 4 only the 80-mg daily dosage of lurasidone hydrochloride was found to be more effective than placebo, and neither 40 mg nor 120 mg could be distinguished from placebo.1,101 Thus, the efficacy of 40-, 80-, 120-, and 160-mg daily dosages of lurasidone hydrochloride was established in these studies as assessed by the change from baseline in the PANSS or BPRSd total scores and the CGI-S.1,2,5,88,100,101 An examination of population subgroups did not reveal any clear evidence of differential responsiveness to the drug based on age, gender, or race.1 An open-label extension study found that the efficacy of lurasidone was maintained for up to 6 months.102
A randomized, double-blind, placebo-controlled withdrawal study examined the efficacy of lurasidone (at flexible dosages of 40-80 mg/day) for maintenance treatment of adults with schizophrenia.103 Patients with schizophrenia who had achieved and maintained clinical stability for at least 12 weeks on lurasidone were randomized to continue lurasidone at their established dosage or switch to placebo for up to 28 weeks.103 In this study, lurasidone substantially delayed the time to relapse compared to placebo.103 An additional 12-month study compared lurasidone (at flexible dosages of 40-160 mg/day) and extended-release quetiapine (at flexible dosages of 200-800 mg/day) for the maintenance treatment of schizophrenia and found that lurasidone was noninferior to extended-release quetiapine in terms of probability of relapse; lurasidone was more effective than extended-release quetiapine for preventing hospitalization and achieving remission.104
Efficacy of lurasidone in the management of schizophrenia in adolescents was established in a placebo-controlled, fixed-dose clinical trial of 6 weeks' duration in patients 13-17 years of age who met DSM-IV-TR criteria for schizophrenia.1,98 Patients were randomized to receive lurasidone 40 mg daily, lurasidone 80 mg daily, or placebo.1,98 The primary endpoint was change in PANSS total score from baseline to week 6; secondary endpoints included change in CGI-S score from baseline to week 6.1,98 At week 6, both dosages of lurasidone were more effective than placebo in reducing PANSS and CGI-S scores.1,98 The 80-mg daily dosage did not provide additional benefit over the 40-mg daily dosage.1 The efficacy of lurasidone was maintained for up to 2 years in an open-label extension study in patients 13-17 years of age.105
The American Psychiatric Association (APA) recommends that patients with schizophrenia be treated with an antipsychotic agent.107 The APA states that, with the possible exception of clozapine, there currently is no definitive evidence that one atypical antipsychotic drug will have superior efficacy compared with another agent in the class, although meaningful differences in response may be observed in individual patients.107 The choice of an antipsychotic agent should be individualized, considering patient preference, past response to therapy, concurrent medical conditions, and medication-specific factors (e.g., adverse effect profile, available formulations, potential drug interactions, receptor binding profiles, pharmacokinetic considerations).107 Patients whose symptoms improve on an antipsychotic drug should continue such treatment long-term; in most patients, it is appropriate to continue the same antipsychotic drug rather than switch to another antipsychotic medication for maintenance therapy.107
Guidelines from the Department of Veterans Affairs and Department of Defense similarly recommend the use of antipsychotic drugs for acute and maintenance treatment of schizophrenia.108 Choice of a specific agent should be based on patient-specific factors and the side effect profiles of the different antipsychotic drugs.108 Clozapine should generally be reserved for individuals with treatment-resistant schizophrenia.108
Depression Associated with Bipolar Disorder
Lurasidone hydrochloride is used as monotherapy for the treatment of major depressive episodes associated with bipolar I disorder (bipolar depression) in adults and pediatric patients 10-17 years of age.1,99 The drug is also used as adjunctive therapy with lithium or valproate for the treatment of major depressive episodes associated with bipolar I disorder in adults.1
Efficacy of lurasidone monotherapy in the treatment of depressive episodes associated with bipolar I disorder was established in a randomized, double-blind, placebo-controlled, multicenter study of 6 weeks' duration in adults who met DSM-IV-TR criteria for major depressive episodes associated with bipolar I disorder, with or without rapid cycling and without psychotic features.1,86 The primary and key secondary end points were the change from baseline to week 6 on the Montgomery-Asberg Depression Rating Scale (MADRS) and the Clinical Global Impressions-Bipolar-Severity of Illness scale (CGI-BP-S) scores, respectively.1,86 Patients were randomized to receive lower-dose lurasidone hydrochloride (flexible dosage range of 20-60 mg daily), higher-dose lurasidone hydrochloride (flexible dosage range of 80-120 mg daily), or placebo.1,86 Lurasidone substantially reduced MADRS and CGI-BP-S scores at week 6 of therapy in both lurasidone dosage groups compared with placebo.1,86 The higher-dose range (80-120 mg daily) of lurasidone hydrochloride was not found to be more effective, on average, than the lower-dose regimen in this study.1,86
Monotherapy in Pediatric Patients
Efficacy of lurasidone as monotherapy for the treatment of depressive episodes associated with bipolar I disorder was established in a randomized, double-blind, placebo-controlled, multicenter study of 6 weeks' duration in patients 10-17 years of age who met DSM-5 criteria for major depressive episodes associated with bipolar I disorder, with or without rapid cycling and without psychotic features.1,99 Patients were randomized to receive lurasidone (flexible dosage of 20-80 mg daily) or placebo.1,99 The primary end point was change from baseline in Children's Depression Rating Scale, Revised (CDRS-R) total score at week 6; the key secondary endpoint was change from baseline in CGI-BP-S depression score at week 6.1,99 Lurasidone substantially reduced CDRS-R total scores and CGI-BP-S depression scores at week 6 compared to placebo.1,99
Adjunctive Treatment in Adults
Efficacy of lurasidone as adjunctive therapy with lithium or valproate in the treatment of depressive episodes associated with bipolar I disorder was established in a randomized, double-blind, placebo-controlled, multicenter study of 6 weeks' duration in adults who met DSM-IV-TR criteria for major depressive episodes associated with bipolar I disorder, with or without rapid cycling and without psychotic features.1,87 Patients who remained symptomatic after lithium or valproate therapy were randomized to receive flexible-dose lurasidone hydrochloride (20-120 mg daily) or placebo.1,87 The primary end point was the change from baseline to week 6 in the MADRS score, and the secondary end point was the change from baseline to week 6 in the CGI-BP-S score.1,87 Lurasidone given as adjunctive therapy with lithium or valproate substantially reduced MADRS and CGI-BP-S scores at week 6 of therapy compared with placebo.1,87
Legacy guidelines from APA published in 2010 state that the first-line pharmacological treatment for bipolar depression is the initiation of either lithium or lamotrigine.109 For severely ill patients, clinicians may initiate simultaneous treatment with lithium and an antidepressant.109 If an acute episode of bipolar depression does not respond to first-line medications at optimal doses, next steps include adding lamotrigine, bupropion, or paroxetine; alternative next steps may include adding other newer antidepressants (e.g., a selective serotonin reuptake inhibitor [SSRI] or venlafaxine) or a monoamine oxidase (MAO) inhibitor.109 The role of antipsychotic medications in the treatment of bipolar depressive episodes without psychotic features is not addressed.109
More recent guidelines from the Department of Veterans Affairs and the Department of Defense published in 2023 recommend quetiapine monotherapy for the treatment of acute bipolar depression; if quetiapine is not selected (based on patient preference and characteristics), cariprazine, lumateperone, lurasidone, or olanzapine monotherapy is recommended.110 The guideline states that there is insufficient evidence to recommend for or against antidepressants or lamotrigine as monotherapy for acute bipolar depression; however, lamotrigine may be used in combination with lithium or quetiapine for the treatment of acute bipolar depression.110 For the prevention of recurrence of bipolar depressive episodes, lamotrigine monotherapy is recommended; other suggested options include lithium or quetiapine monotherapy.110 If lithium or quetiapine is not selected based on patient preference and characteristics, olanzapine monotherapy is suggested as an alternative; olanzapine, lurasidone, or quetiapine may also be used in combination with lithium or valproate for the prevention of recurrent bipolar depressive episodes.110
Lurasidone hydrochloride has been used for the treatment of major depressive disorder with mixed features (subthreshold hypomanic symptoms)†.106 In a randomized, double-blind, placebo-controlled trial of 6 weeks' duration, lurasidone (at flexible dosages of 20-60 mg/day) was more effective than placebo for improving depressive symptoms and overall illness severity in patients with major depressive disorder, a current major depressive episode, and 2-3 protocol-defined manic symptoms.106
Dispensing and Administration Precautions
Lurasidone hydrochloride is commercially available as tablets, which are administered orally once daily, usually in the morning or evening, and should be taken with food (containing at least 350 calories) to increase absorption.1 Food increases peak concentrations and AUC of lurasidone threefold and twofold, respectively; however, lurasidone exposure was not affected as meal size was increased from 350 to 1000 calories and was independent of meal fat content.1 Lurasidone was administered with food in the controlled clinical studies.1
Store lurasidone tablets at 25°C; excursions permitted to 15-30°C.1
Dosage of lurasidone hydrochloride is expressed in terms of the hydrochloride salt.1
For the acute management of schizophrenia in adolescents 13-17 years of age, the recommended initial dosage of lurasidone hydrochloride is 40 mg orally once daily.1 Initial dosage titration is not required.1 Dosages ranging from 40-80 mg daily were effective in a 6-week controlled trial.1 The maximum recommended dosage of lurasidone hydrochloride for the treatment of schizophrenia is 80 mg daily.1
The manufacturer states that efficacy of lurasidone in schizophrenia beyond 6 weeks has not been established in controlled studies.1 If lurasidone is used for an extended period, the long-term usefulness of the drug for the individual patient should be reassessed periodically.1
Depression Associated with Bipolar Disorder
For the management of depressive episodes associated with bipolar I disorder in pediatric patients 10-17 years of age as monotherapy, the recommended initial dosage of lurasidone hydrochloride is 20 mg orally once daily.1 Initial dosage titration is not required.1 The dosage may be increased after 1 week based on clinical response.1 Dosages ranging from 20-80 mg daily as monotherapy were effective in a 6-week controlled study.1 By the end of monotherapy study, the majority of patients (67%) were receiving 20 or 40 mg daily.1 The maximum recommended dosage of lurasidone hydrochloride for the treatment of bipolar depression as monotherapy is 80 mg daily.1
The manufacturer states that efficacy of lurasidone in bipolar depression beyond 6 weeks has not been established in controlled studies.1 If lurasidone is used for an extended period, the long-term usefulness of the drug for the individual patient should be reassessed periodically.1
Efficacy of lurasidone for the treatment of mania associated with bipolar disorder is not established.1
For the acute management of schizophrenia in adults, the recommended initial dosage of lurasidone hydrochloride is 40 mg orally once daily.1 Initial dosage titration is not required.1 Dosages ranging from 40-160 mg daily were effective in 6-week controlled trials.1 The maximum recommended dosage of lurasidone hydrochloride for the treatment of schizophrenia is 160 mg daily.1
The manufacturer states that efficacy of lurasidone in schizophrenia beyond 6 weeks has not been established in controlled studies.1 If lurasidone is used for an extended period, the long-term usefulness of the drug for the individual patient should be reassessed periodically.1
Depression Associated with Bipolar Disorder
For the management of depressive episodes associated with bipolar I disorder in adults, either as monotherapy or as adjunctive therapy with lithium or valproate, the recommended initial dosage of lurasidone hydrochloride is 20 mg orally once daily.1 Initial dosage titration is not required.1 Dosages ranging from 20-120 mg daily as monotherapy or as adjunctive therapy with lithium or valproate were effective in 6-week controlled studies.1 In the monotherapy study, the higher dosage range (80-120 mg daily) did not provide additional efficacy, on average, over the lower dosage range (20-60 mg daily).1 The maximum recommended dosage of lurasidone hydrochloride for the treatment of bipolar depression, either as monotherapy or as adjunctive therapy with lithium or valproate, is 120 mg daily.1
The manufacturer states that efficacy of lurasidone in bipolar depression beyond 6 weeks has not been established in controlled studies.1 If lurasidone is used for an extended period, the long-term usefulness of the drug for the individual patient should be reassessed periodically.1
Dosage Modifications Due to Concomitant Use of Drugs Affecting Hepatic Microsomal Enzymes
In patients receiving lurasidone and in whom a moderate inhibitor of cytochrome P-450 (CYP) isoenzyme 3A4 (e.g., atazanavir, diltiazem, erythromycin, fluconazole, verapamil) will be added to therapy, the lurasidone dosage should be reduced to 50% of the original dosage.1 Similarly, in patients receiving a moderate CYP3A4 inhibitor in whom lurasidone hydrochloride is initiated, the recommended initial dosage of lurasidone hydrochloride is 20 mg daily and the maximum recommended dosage is 80 mg daily.1 If lurasidone is used concurrently with a moderate CYP3A4 inducer (e.g., bosentan, efavirenz, etravirine, modafinil, nafcillin), it may be necessary to increase the lurasidone dosage after chronic therapy (i.e., ≥7 days) with the CYP3A4 inducer.1 Lurasidone should not be given concurrently with strong CYP3A4 inhibitors (e.g., clarithromycin, ketoconazole, ritonavir, voriconazole) or strong CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin, St. John's wort [ Hypericum perforatum ]).1
The manufacturer recommends dosage adjustment in patients with moderate (Child-Pugh score 7-9) or severe hepatic impairment (Child-Pugh score 10-15).1 The recommended initial lurasidone hydrochloride dosage in these patients is 20 mg daily.1 The manufacturer states that lurasidone hydrochloride dosage in patients with moderate hepatic impairment should not exceed 80 mg daily and that dosage should not exceed 40 mg daily in patients with severe hepatic impairment.1 The manufacturer makes no specific dosage recommendations for patients with mild hepatic impairment.1
The manufacturer recommends dosage adjustment in patients with moderate (creatinine clearance from 30 to <50 mL/minute) or severe renal impairment (creatinine clearance <30 mL/minute).1 The recommended initial lurasidone hydrochloride dosage in these patients is 20 mg daily.1 The maximum recommended dosage in patients with moderate or severe renal impairment is 80 mg daily.1 The manufacturer makes no specific dosage recommendations for patients with mild renal impairment.1
The manufacturer states that it is not known whether dosage adjustment is necessary in geriatric patients on the basis of age alone.1
Increased Mortality in Geriatric Patients with Dementia-Related Psychosis
A boxed warning is included in the prescribing information for lurasidone concerning the increased risk of death in geriatric patients with dementia-related psychosis treated with antipsychotic drugs.1 Analyses of 17 placebo-controlled trials (modal duration of 10 weeks) revealed a 1.6- to 1.7-fold increase in mortality among geriatric patients who were mainly receiving atypical antipsychotic drugs (i.e., aripiprazole, olanzapine, quetiapine, risperidone) compared with that observed in patients receiving placebo.1 Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5% compared with a rate of about 2.6% in the placebo group.1 Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature.1 The manufacturer states that lurasidone is not approved for the treatment of patients with dementia-related psychosis.1
Suicidal Thoughts and Behaviors in Pediatric and Young Adult Patients
A boxed warning is included in the prescribing information for lurasidone regarding the increased risk of suicidal thoughts and behaviors in pediatric and young adult patients receiving antidepressants.1 Pooled data from placebo-controlled studies of antidepressants (i.e., selective serotonin reuptake inhibitors [SSRIs] and other antidepressant classes) found an increased incidence of suicidal thoughts and behaviors in pediatric and young adult patients receiving antidepressants compared to placebo.1 Approximately 77,000 adults and >4400 pediatric patients were included in the pooled analysis.1 An increased risk of suicidal thoughts and behaviors was not demonstrated with antidepressants compared with placebo in adults >24 years of age, and a reduced risk was observed in adults ≥65 years of age.1 No suicides occurred in any of the pediatric studies.1 Suicides did occur in studies of adult patients, although the number of suicides was not sufficient to draw conclusions in this population.1 It is unknown if the risk of suicidal thoughts and behaviors in pediatric and young adult patients extends to longer-term use (i.e., beyond 4 months) of antidepressant therapy.1
All patients receiving antidepressant therapy should be monitored for clinical worsening and the emergence of suicidal thoughts or behaviors, especially during the first few months of treatment and when the dosage is adjusted.1 Family members or caregivers of patients should be counseled to monitor for behavioral changes and to alert their healthcare provider if these occur.1 Consider changing the or possibly discontinuing lurasidone in those with persistently worsening depression or who are experiencing emergent suicidal thoughts or behaviors.1
Other Warnings and Precautions
Cerebrovascular Events in Geriatric Patients with Dementia-related Psychosis
An increased incidence of adverse cerebrovascular events (cerebrovascular accidents and transient ischemic attacks), including fatalities, has been observed in geriatric patients with dementia-related psychosis treated with certain atypical antipsychotic agents (aripiprazole, olanzapine, risperidone) in placebo-controlled studies.1 The manufacturer states that lurasidone is not approved for the treatment of patients with dementia-related psychosis.1
Neuroleptic Malignant Syndrome
Neuroleptic malignant syndrome (NMS), a potentially fatal syndrome requiring immediate discontinuance of the drug and intensive symptomatic treatment, has been reported in patients receiving antipsychotic agents, including lurasidone.1 Clinical signs and symptoms include hyperpyrexia, muscle rigidity, altered mental status, autonomic instability, in addition to possible elevations in creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.1
If NMS is suspected, immediately discontinue lurasidone and provide intensive symptomatic treatment and monitoring.1
Because use of antipsychotic agents, including lurasidone, may be associated with tardive dyskinesia (a syndrome of potentially irreversible, involuntary, dyskinetic movements), lurasidone should be prescribed in a manner that is most likely to minimize the occurrence of this syndrome.1 Chronic antipsychotic treatment generally should be reserved for patients who suffer from a chronic illness that is known to respond to antipsychotic agents, and for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate.1 In patients who do require chronic treatment, the lowest dosage and the shortest duration of treatment producing a satisfactory clinical response should be sought, and the need for continued treatment should be reassessed periodically.1
If signs and symptoms of tardive dyskinesia appear in a lurasidone-treated patient, lurasidone discontinuance should be considered; however, some patients may require continued treatment with the drug despite the presence of the syndrome.1
Atypical antipsychotic agents have been associated with metabolic changes that may increase cardiovascular and cerebrovascular risk, including hyperglycemia, dyslipidemia, and body weight gain.1 While all of these drugs produce some metabolic changes, each drug has its own specific risk profile.1
Hyperglycemia and Diabetes Mellitus
Hyperglycemia, sometimes severe and associated with ketoacidosis, hyperosmolar coma, or death, has been reported in patients receiving atypical antipsychotic agents.1 In short- and longer-term clinical trials in adult patients with schizophrenia or bipolar depression, clinically important differences between lurasidone and placebo in mean change from baseline to end point in serum glucose concentrations were not observed.1 It remains to be determined whether lurasidone also is associated with this increased risk.1
The manufacturer states that patients with preexisting diabetes mellitus in whom therapy with an atypical antipsychotic is initiated should be periodically monitored for worsening of glucose control; those with risk factors for diabetes (e.g., obesity, family history of diabetes) should undergo fasting blood glucose testing upon therapy initiation and periodically throughout treatment.1 Any patient who develops manifestations of hyperglycemia (including polydipsia, polyuria, polyphagia, and weakness) during treatment with an atypical antipsychotic should undergo fasting blood glucose testing.1 In some cases, patients who developed hyperglycemia while receiving an atypical antipsychotic have required continuance of antidiabetic treatment despite discontinuance of the suspect drug; in other cases, hyperglycemia resolved with discontinuance of the antipsychotic.1
Undesirable changes in lipid parameters have been observed in patients treated with some atypical antipsychotic agents; however, lurasidone generally does not appear to adversely affect the lipid profile in patients receiving the drug.1 In a between-group comparison of pooled data from short-term, placebo-controlled studies, there were no clinically important changes in mean fasting total cholesterol and triglyceride concentrations from baseline to end point in the lurasidone-treated patients.1 In uncontrolled, longer-term schizophrenia studies in adults, lurasidone was associated with decreases from baseline in mean total cholesterol and triglyceride concentrations of 3.8 and 15.1 mg/dL at week 24, 3.1 and 4.8 mg/dL at week 36, and 2.5 and 6.9 mg/dL at week 52, respectively.1 In an uncontrolled, longer-term bipolar depression study in adults, lurasidone monotherapy was associated with decreases from baseline in mean total cholesterol and triglyceride concentrations of 0.5 and 1 mg/dL at week 24, respectively.1 In an uncontrolled, longer-term bipolar depression study of lurasidone given as adjunctive therapy with lithium or valproate in adults, lurasidone was associated with a decrease in mean total cholesterol concentrations of 0.9 mg/dL and a mean increase in triglyceride concentrations of 5.3 mg/dL at week 24.1 In a short-term study of adolescents with schizophrenia, lurasidone therapy was associated with a decrease in fasting cholesterol of 4.4 mg/dL and an increase of 1.6 mg/dL in patients receiving dosages of 40 mg daily and 80 mg daily, respectively.1 Fasting triglyceride concentrations decreased 0.6 mg/dL in patients receiving 40 mg daily of lurasidone and increased 8.5 mg/dL in patients receiving 80 mg daily of lurasidone.1 In a short-term study of pediatric patients 10-17 years of age with bipolar depression receiving lurasidone monotherapy at dosages of 20-80 mg daily, lurasidone was associated with a decrease in mean fasting cholesterol concentrations of 6.3 mg/dL and a mean decrease in fasting triglyceride concentrations of 7.6 mg/dL at week 6.1 During a long-term 104-week study of pediatric patients 6-17 years of age with schizophrenia, bipolar depression, or autistic disorder, lurasidone was associated with increases in total cholesterol in 12% of patients, LDL cholesterol increases in 3%, and decreases in HDL cholesterol in 27% of patients by the end of the study.1 Triglyceride levels also increased in 12% of patients with normal levels at baseline.1
Weight gain has been observed with atypical antipsychotic therapy.1 The manufacturer recommends clinical monitoring of weight in patients receiving lurasidone.1
Differences in mean weight gain between lurasidone-treated patients and placebo recipients were reported in short-term schizophrenia clinical studies.1 A mean weight gain of 0.43 kg was reported in lurasidone-treated patients compared with a loss of 0.02 kg in those receiving placebo; 4.8% of lurasidone-treated patients gained 7% or more of their baseline body weight compared with 3.3% of those receiving placebo.1 During uncontrolled, longer-term schizophrenia studies, lurasidone therapy was associated with a mean weight loss of 0.69 kg at week 24, 0.59 kg at week 36, and 0.73 kg at week 52.1
The mean weight gain during a short-term study in adult patients receiving lurasidone as monotherapy for bipolar depression was 0.29 kg compared with a loss of 0.04 kg in those receiving placebo; 2.4% of lurasidone-treated patients gained 7% or more of their baseline body weight compared with 0.7% of those receiving placebo.1 During an uncontrolled, longer-term extension of this study, lurasidone monotherapy was associated with a mean weight loss of 0.02 kg at week 24.1 In the short-term studies of lurasidone as adjunctive therapy with lithium or valproate in adults, lurasidone was associated with a mean weight gain of 0.11 kg compared with a gain of 0.16 kg in those receiving placebo.1 During an uncontrolled, longer-term bipolar depression study, lurasidone, given as adjunctive therapy with lithium or valproate, was associated with a mean weight gain of 1.28 kg at week 24.1 The mean weight gain during a short-term study in adolescents receiving lurasidone as monotherapy for schizophrenia was 0.5 kg compared to 0.2 kg with placebo.1 The mean weight gain during a short-term study in pediatric patients 10-17 years of age receiving lurasidone as monotherapy for bipolar depression was 0.7 kg compared with an increase of 0.5 kg in those receiving placebo.1 During a long-term, 104-week study that enrolled pediatric patients 6-17 years of age with schizophrenia, bipolar depression, or autistic disorder, the mean weight gain was 5.85 kg.1 Over half (54%) of 701 patients in the study were receiving lurasidone.1 When adjusted for normal growth patterns based on z-score, the mean change in z-score was -0.06 standard deviations (SD) for body weight and -0.13 SD for body mass index (BMI), indicating minimal deviations from the normal growth curve.1
Similar to other antipsychotic agents and drugs with dopamine D2 antagonistic activity, lurasidone can elevate serum prolactin concentrations.1
In short-term schizophrenia clinical trials in adults, the median change from baseline to end point in prolactin concentrations for lurasidone-treated patients was an increase of 0.4 ng/mL compared with a decrease of 1.9 ng/mL in the placebo group.1 The proportion of adult patients with prolactin elevations ≥5 times the upper limit of normal (ULN) was 2.8% for lurasidone-treated patients compared with 1% for placebo recipients.1 In short-term bipolar depression trials in adults, the median increase from baseline to end point in prolactin concentrations was 1.7 and 3.5 ng/mL in the lower- and higher-dosage lurasidone monotherapy groups, respectively, compared with an increase of 0.3 ng/mL in the placebo group.1 In the clinical study of lurasidone as adjunctive therapy with lithium or valproate in adults, the median increase in prolactin was 2.8 ng/mL in the lurasidone-treated patients compared with no change in the placebo recipients.1 The increase in prolactin was generally greater in female patients than male patients.1 In a short-term schizophrenia study in adolescents, the proportion of patients with prolactin elevations ≥5 times ULN was 0.5% for lurasidone-treated patients compared with 1% for placebo recipients.1 In a short-term bipolar depression study of pediatric patients 10-17 years of age, there were no patients receiving lurasidone who experienced prolactin elevations ≥5 times ULN.1 During a long-term, 104-week study of pediatric patients 6-17 years of age, prolactin elevations ≥5 times ULN occurred in 2% of patients overall (3% females and 1% males).1 Clinical disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been associated with prolactin-elevating drugs.1 In addition, chronic hyperprolactinemia associated with hypogonadism may lead to decreased bone density in both female and male patients.1
If lurasidone therapy is considered in a patient with previously detected breast cancer, clinicians should consider that approximately one-third of human breast cancers are prolactin-dependent in vitro.1 However, current epidemiologic studies report inconsistent findings of a relationship between hyperprolactinemia and breast cancer onset.1
Leukopenia, Neutropenia, and Agranulocytosis
Leukopenia and neutropenia have been reported with antipsychotic agents, including lurasidone.1 Agranulocytosis (including fatal cases) also has been reported with other antipsychotic agents.1
Possible risk factors for leukopenia and neutropenia include preexisting low leukocyte count and a history of drug-induced leukopenia and neutropenia.1 Patients with a preexisting low leukocyte count or a history of drug-induced leukopenia or neutropenia should have their complete blood count monitored frequently during the first few months of therapy.1 Lurasidone should be discontinued at the first sign of a decline in leukocyte count in the absence of other causative factors.1
Patients with neutropenia should be carefully monitored for fever or other signs or symptoms of infection and promptly treated if such signs and symptoms occur.1 In patients with severe neutropenia (absolute neutrophil count [ANC] less than 1000/mm3), lurasidone should be discontinued and the leukocyte count monitored until recovery occurs.1
Orthostatic Hypotension and Syncope
Orthostatic hypotension, dizziness, lightheadedness, tachycardia or bradycardia, and syncope may occur during lurasidone therapy in some patients, particularly early in treatment and when dosage is increased, perhaps because of the drug's α1-adrenergic blocking activity.1 Patients at increased risk of these adverse reactions or of developing complications from hypotension include those with dehydration, hypovolemia, a history of cardiovascular disease (e.g., heart failure, myocardial infarction, ischemic heart disease, conduction abnormalities), or a history of cerebrovascular disease, as well as patients receiving concomitant antihypertensive therapy and those who are antipsychotic-naive.1
In short-term schizophrenia trials in adults, orthostatic hypotension was reported as an adverse event in 0.3% of patients receiving lurasidone compared with 0.1% of placebo recipients, and syncope was reported in 0.1% of patients receiving lurasidone compared with none of the placebo recipients.1 Orthostatic hypotension, as assessed by vital signs, was reported in 0.8, 2.1, 1.7, and 0.8% of adult patients receiving lurasidone hydrochloride 40, 80, 120, and 160 mg daily, respectively, compared with 0.7% of patients receiving placebo in short-term schizophrenia trials.1 The incidence of orthostatic hypotension reported as adverse events was 0.5% in adolescent patients receiving lurasidone compared with 0% of placebo recipients in a short-term schizophrenia study.1
There were no reports of orthostatic hypotension or syncope as adverse events in short-term bipolar depression clinical trials in adults.1 Orthostatic hypotension, as assessed by vital signs, occurred in 0.6-1.1% of lurasidone-treated patients compared with 0-0.9% of the placebo recipients in these trials.1 In a short-term study in bipolar depression, orthostatic hypotension, as assessed by vital signs, was reported in 1.1% of pediatric patients 10-17 years of age receiving lurasidone compared to 0.6% of placebo recipients.1
The manufacturer recommends considering use of a lower initial lurasidone dosage and more gradual dosage titration in patients with a history of cardiovascular disease (e.g., heart failure, history of myocardial infarction, ischemic heart disease, conduction abnormalities) or cerebrovascular disease or with conditions that would predispose patients to hypotension (e.g., dehydration, hypovolemia, concomitant antihypertensive therapy) and in antipsychotic-naive patients.1 In addition, orthostatic vital signs should be monitored in such patients.1
Treatment with lurasidone may result in somnolence, postural hypotension, and motor and sensory instability, which can lead to falls and, potentially, fractures or other injuries.1 Complete fall risk assessments when initiating lurasidone in those with diseases, conditions, or medications that could exacerbate the risk of falls.1 In patients receiving long-term antipsychotic therapy, fall risk should be assessed on an ongoing basis.1
In adult short-term schizophrenia trials, seizures occurred in 0.1% of patients receiving lurasidone compared with 0.1% of patients receiving placebo.1 There were no reports of seizures or convulsions in lurasidone-treated patients in short-term bipolar depression trials in adults and pediatric patients.1
As with other antipsychotic agents, lurasidone should be used with caution in patients with a history of seizures or with conditions that lower the seizure threshold (e.g., dementia of the Alzheimer's type); conditions that lower the seizure threshold may be more prevalent in patients ≥65 years of age.1
Cognitive and Motor Impairment
Like other antipsychotic agents, lurasidone potentially may impair judgment, thinking, or motor skills.1 In short-term, placebo-controlled schizophrenia trials in adults, somnolence (including hypersomnia, hypersomnolence, and sedation) was reported in 17% of patients receiving lurasidone compared with 7.1% of placebo recipients.1 In a short-term adolescent schizophrenia study, somnolence was reported in 14.5% of patients receiving lurasidone compared to 7.1% of placebo recipients.1 In a short-term bipolar depression trial in adults, somnolence was reported in 7.3 and 13.8% of patients who received lower-dose (20-60 mg daily) and higher-dose (80-120 mg daily) lurasidone hydrochloride monotherapy, respectively, compared with 6.5% of placebo recipients.1 Frequency of somnolence was found to be dose related in the monotherapy study.1 In a short-term bipolar depression study in pediatric patients 10-17 years of age, somnolence was reported in 11.4% of patients receiving lurasidone compared to 5.8% of placebo recipients.1
Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents.1 The manufacturer recommends appropriate caution when lurasidone is used in patients who will be experiencing conditions that may contribute to an elevation in core body temperature (e.g., strenuous exercise, extreme heat, concomitant use of agents with anticholinergic activity, dehydration).1
Antidepressants can increase the risk of developing manic or hypomanic episodes, particularly in patients with bipolar disorder.1 Manic or hypomanic episodes were reported in <1% of patients receiving lurasidone and in <1% of patients receiving placebo in the adult bipolar depression monotherapy and adjunctive therapy studies.1 Patients should be monitored for the emergence of manic or hypomanic episodes during lurasidone therapy.1
Esophageal dysmotility and aspiration have been associated with the use of antipsychotic agents.1 Aspiration pneumonia is a common cause of morbidity and mortality in geriatric patients, particularly in those with advanced Alzheimer's dementia.1 Lurasidone is not approved for the treatment of patients with dementia-related psychosis and should be used with caution in patients at risk for aspiration pneumonia.1
Neurologic Adverse Reactions in Patients with Parkinsonian Syndrome or Dementia with Lewy Bodies
Patients with parkinsonian syndrome or dementia with Lewy bodies reportedly have an increased sensitivity to antipsychotic agents.1 Clinical manifestations of this increased sensitivity have been reported to include confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and features consistent with NMS.1
A pregnancy registry is available that monitors pregnancy outcomes in women exposed to lurasidone during pregnancy.1 For more information, contact the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visit [Web].1
Neonates exposed to antipsychotic agents during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery.1 Symptoms reported to date have included agitation, hypertonia, hypotonia, tardive dyskinetic-like symptoms, tremor, somnolence, respiratory distress, and feeding disorder.1 Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage appropriately.1 The symptoms have varied in severity; some neonates recovered within hours to days without specific treatment while others have required prolonged hospitalization.1
Lactation studies have not been conducted to assess the presence of lurasidone in human milk.1 The effects of lurasidone on the breast-fed infant or on milk production are not known.1 Lurasidone is distributed into milk in rats.1 The developmental and health benefits of breast-feeding should be weighed along with the mother's clinical need for the drug and any potential adverse effects on the breast-fed infant from lurasidone or from the underlying maternal condition.1
Safety and effectiveness of lurasidone 40-80 mg daily for the treatment of schizophrenia have been established in adolescent patients 13-17 years of age.1 Safety and efficacy for this indication was established in a 6-week, placebo-controlled study in 326 adolescent patients.1 Safety and efficacy of lurasidone for schizophrenia have not been established in pediatric patients <13 years of age.1
Safety and efficacy of lurasidone 20-80 mg daily for the treatment of bipolar depression have been established in pediatric patients 10-17 years of age.1 Safety and efficacy for this indication was established in a 6-week, placebo-controlled study in 347 pediatric patients.1 Safety and efficacy of lurasidone for bipolar depression have not been established in pediatric patients <10 years of age.1
Efficacy of lurasidone for the treatment of irritability associated with autistic disorder have not been established in pediatric patients.1 Treatment with lurasidone 20 mg daily and 60 mg daily failed to demonstrate efficacy in a 6-week study in pediatric patients 6-17 years of age with irritability associated with autistic disorder diagnosed by Diagnostic and Statistical Manual of Mental Disorders, 4th Ed. (DSM-IV) criteria.1 The primary endpoint of an improvement from baseline in the irritability subscale of the Aberrant Behavior Checklist (ABC) was not met at 6 weeks.1
In long term (104-week), open-label study of pediatric patients 6-17 years of age with schizophrenia, bipolar depression, or autistic disorder, z-scores were derived for height based on standardized growth curves adjusted for age and sex.1 There was minimal deviation from the growth curve in the study.1
Clinical trial experience with lurasidone in patients with schizophrenia who are ≥65 years of age is insufficient to determine whether they respond differently than younger adults.1
In geriatric patients (65-85 years of age) with psychosis, serum lurasidone concentrations were similar to those observed in younger adults.1 The manufacturer states that it is unknown whether dosage adjustment is necessary in geriatric patients on the basis of age alone.1
Geriatric patients with dementia-related psychosis treated with lurasidone are at an increased risk of death compared with those treated with placebo.1 In addition, an increased incidence of adverse cerebrovascular events (cerebrovascular accidents and transient ischemic attacks), including fatalities, has been observed in geriatric patients with dementia-related psychosis treated with certain atypical antipsychotic agents (aripiprazole, olanzapine, risperidone) in placebo-controlled studies.1 The manufacturer states that lurasidone is not approved for the treatment of patients with dementia-related psychosis.
In pooled data analyses, a reduced risk of suicidality was observed in adults ≥65 years of age with antidepressant therapy compared with placebo.1
Patients with moderate to severe hepatic impairment (Child-Pugh score ≥7) have greater exposure to lurasidone than patients with normal hepatic function, which may increase the risk of adverse reactions associated with lurasidone.1 Dosage adjustment is recommended for patients with moderate or severe hepatic impairment.1
Patients with moderate or severe renal impairment (creatinine clearance <50 mL/minute) have greater exposure to lurasidone than patients with normal renal function, which may increase the risk of adverse reactions associated with lurasidone.1 Dosage adjustment is recommended for patients with moderate or severe renal impairment (creatinine clearance <50 mL/minute).1
Adverse effects occurring in ≥5% of adult patients receiving lurasidone for schizophrenia and at a frequency at least twice that reported with placebo include somnolence (including hypersomnia, hypersomnolence, and sedation), akathisia, extrapyramidal symptoms (including parkinsonian symptoms and dyskinesia), and nausea.1
Adverse effects occurring in ≥5% of adolescent patients (13-17 years of age) receiving lurasidone for schizophrenia and at a frequency at least twice that reported with placebo include somnolence (including hypersomnia, hypersomnolence, and sedation), nausea, akathisia, extrapyramidal symptoms (non-akathisia), rhinitis (80 mg dosage only) and vomiting.1
Adverse effects occurring in ≥5% of adult patients receiving lurasidone for bipolar depression as monotherapy or as adjunctive therapy with lithium or valproate and at a frequency at least twice that reported with placebo include somnolence (including hypersomnia, hypersomnolence, and sedation), akathisia, and extrapyramidal symptoms (including parkinsonian symptoms and dyskinesia).1
Adverse effects occurring in ≥5% of pediatric patients (10-17 years of age) receiving lurasidone as monotherapy for bipolar depression and at a frequency at least twice that reported with placebo include nausea, weight increase, and insomnia.1
Lurasidone is primarily metabolized by cytochrome P-450 (CYP) isoenzyme 3A4.1 Lurasidone is not a substrate of CYP isoenzymes 1A1, 1A2, 2A6, 4A11, 2B6, 2C8, 2C9, 2C19, 2D6, or 2E1.1 Lurasidone is not a substrate of organic anion transporter polypeptide (OATP) 1B1 or OATP1B3, but is likely a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP).1 Lurasidone is not expected to inhibit OATP1B1, OATP1B3, organic cation transporter (OCT) 1, OCT2, organic anion transporter (OAT)1, OAT3, multidrug and toxin extrusion transporter (MATE)1, MATE2K, or bile salt exporter pump (BSEP) at clinically relevant concentrations.1 Lurasidone is not a clinically important inhibitor of P-gp, but may inhibit BCRP.1
Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes
CYP3A4 Inhibitors and Inducers
Lurasidone is predominantly metabolized by CYP3A4.1 Pharmacokinetic interactions of lurasidone with strong and moderate inhibitors or strong inducers of CYP3A4 have been observed.1
Lurasidone should not be used in combination with strong inhibitors (e.g., clarithromycin, ketoconazole, ritonavir, voriconazole) or strong inducers (e.g., carbamazepine, phenytoin, rifampin, St. John's wort [ Hypericum perforatum ]) of CYP3A4.1 Lurasidone dosage should be adjusted when used concurrently with moderate CYP3A4 inhibitors (e.g., atazanavir, diltiazem, erythromycin, fluconazole, verapamil).1
If lurasidone is used concurrently with a moderate CYP3A4 inducer (e.g., bosentan, efavirenz, etravirine, modafinil, nafcillin), an increase in lurasidone dosage may be necessary after chronic therapy (i.e., ≥7 days) with the CYP3A4 inducer.1
A potential pharmacologic interaction exists (possible disruption of body temperature regulation)1
Concomitant use of diltiazem, a moderate CYP3A4 inhibitor, with lurasidone can increase lurasidone exposure.1 If diltiazem is initiated in patients receiving lurasidone, the manufacturer states that lurasidone dosage should be reduced to 50% of the original dosage.1 If lurasidone is initiated in patients receiving diltiazem, the manufacturer recommends that lurasidone hydrochloride therapy be initiated at 20 mg daily and that dosage not exceed 80 mg daily.1
Grapefruit and grapefruit juice should be avoided in patients receiving lurasidone since they may inhibit CYP3A4 and increase plasma concentrations of lurasidone.1
Because of its α1-adrenergic blocking activity, the manufacturer states that patients receiving lurasidone may be at increased risk of orthostatic hypotension and syncope and related adverse effects.1
Ketoconazole, a strong CYP3A4 inhibitor, should not be used concurrently with lurasidone.1
Concomitant use of lithium 300-2400 mg daily with lurasidone for up to 6 weeks has minimal effect on lurasidone exposure.1 Population pharmacokinetic analyses also indicate that concomitant use of lurasidone has minimal effect on lithium exposure when lithium is administered at dosages of 300-2400 mg daily.1 Lurasidone dosage adjustment is not required in patients receiving lithium concurrently.1
Concomitant use of lurasidone with rifampin a strong CYP3A4 inducer, results in decreased lurasidone exposure.1 Avoid concomitant use of rifampin with lurasidone.1
Lurasidone should not be used concurrently with St. John's wort ( Hypericum perforatum ), a strong inducer of CYP3A4.1
Concomitant use of valproate 300-2000 mg daily with lurasidone for up to 6 weeks has minimal effect on lurasidone exposure.1 Population pharmacokinetic analyses also indicate that concomitant use of lurasidone has minimal effect on valproate exposure when valproate is administered at dosages of 300-2000 mg daily.1 Therefore, no dosage adjustment of lurasidone is necessary in patients receiving concomitant lurasidone.1
Lurasidone is a benzisothiazol-derivative antipsychotic agent and has been referred to as an atypical antipsychotic agent.1 Although the exact mechanism of action of lurasidone in schizophrenia and bipolar depression is unknown, it has been suggested that the efficacy of lurasidone is mediated through a combination of antagonist activity at central dopamine type 2 (D2) and serotonin type 2 (5-hydroxytryptamine [5-HT2A]) receptors.1
Lurasidone is an antagonist that exhibits high affinity for D2, 5-HT2A, and 5-HT7 receptors and moderate affinity for α2C-adrenergic receptors in vitro.1 The drug acts as a partial agonist at 5-HT1A receptors and is an antagonist at α2A-adrenergic receptors in vitro.1 Lurasidone exhibits affinity for α1-adrenergic receptors and little or no affinity for histamine (H1) receptors and muscarinic (M1) receptors.1
Pharmacokinetics of lurasidone are dose proportional over the total daily dosage range of 20-160 mg.1 Lurasidone is rapidly absorbed following oral administration and reaches peak serum concentrations within about 1-3 hours.1 Peak plasma concentrations and AUC increase by 3-fold and 2-fold, respectively, when lurasidone is administered with food compared to fasting conditions.1 In clinical studies that established the safety and efficacy of the drug, patients were instructed to take lurasidone with food.1 Approximately 9-19% of an administered dose is absorbed orally.1 Steady-state concentrations of the drug are achieved within 7 days.1 Lurasidone exposure is generally similar in children and adolescents (10-17 years of age) compared to adults across the oral dosage range of 40-160 mg, without adjusting for body weight.1 Lurasidone is highly bound (approximately 99%) to serum proteins.1 The drug is metabolized mainly via cytochrome P-450 (CYP) 3A4.1 The major biotransformation pathways are oxidative N -dealkylation, hydroxylation of the norbornane ring, and S -oxidation.1 Lurasidone is metabolized into 2 active metabolites (ID-14283 and ID-14326) and 2 major inactive metabolites (ID-20219 and ID-20220).1 Following administration of a single radiolabeled dose of lurasidone, approximately 80 and 9% of the dose is excreted in feces and urine, respectively.1 The mean elimination half-life of lurasidone is 18 hours.1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
1. Sumitomo Pharma America Inc. Latuda® (lurasidone hydrochloride) tablets prescribing information. Marlborough, MA; 2025 Jan.
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