Clinical Studies

Two double-blind, randomized, placebo-controlled, six-week clinical trials established the efficacy of LATUDA for the treatment of adult patients with bipolar I disorder, both as monotherapy and as adjunctive therapy with lithium or valproate. Both studies showed that treatment with LATUDA resulted in statistically significant reductions in Montgomery-Åsberg Depression Rating Scale (MADRS) scores at 6 weeks compared to placebo.1,2

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Lurasidone Monotherapy in the Treatment of Bipolar I Depression: A Randomized, Double-Blind, Placebo-Controlled Study

Loebel A, Cucchiaro J, Silva R, Kroger H, Hsu J, Sarma K, Sachs G.

Am J Psychiatry. 2014;171:160-168.

Objective1

  • Evaluate the efficacy and safety of LATUDA as monotherapy in the treatment of patients with major depressive episodes associated with bipolar I disorder

Study design1

  • Patients were randomized to receive double-blind treatment with LATUDA 20–60 mg/day
    (n=166), 80–120 mg/day (n=169), or placebo (n=170) for 6 weeks

Dosing1

  • Patients assigned to receive LATUDA underwent a fixed titration period for one week, before flexible dosing:
    • LATUDA 20–60 mg group: 20 mg/day for Days 1 to 7
    • LATUDA 80–120 mg group: 20 mg/day for Days 1 to 2; 40 mg/day for Days 3 to 4; 60 mg/day for Days 5 to 6; 80 mg/day on Day 7
  • Flexible dosing of LATUDA within the assigned dosing range was permitted after Day 7 at weekly intervals in 20-mg increments/decrements to optimize efficacy and tolerability
  • LATUDA or placebo was taken once daily in the evening, with a meal or within 30 minutes after eating

Endpoints1

  • Primary: Mean change from baseline to Week 6 in Montgomery-Åsberg Depression Rating Scale (MADRS) scores
  • Key secondary: Mean change from baseline to Week 6 in CGI-BP depression scores

Summary of results1

  • LATUDA 20–60 mg/day and 80–120 mg/day groups had significantly reduced mean MADRS total scores at Week 6 compared with the placebo group
  • LATUDA resulted in significantly greater reduction in CGI-BP depression scores at Week 6 compared with placebo
  • Discontinuation rates due to adverse events were similar in LATUDA 20–60 mg/day (6.6%) and
    80–120 mg/day (5.9%) groups and comparable to placebo group (6.5%)
  • Minimal changes in weight, lipids, and glucose were observed during treatment with LATUDA

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Chapter 2: Study Design

Mood disorder specialist Dr. Joseph R. Calabrese describes the study design used in the LATUDA monotherapy clinical trial in this video.

References:
1. Loebel A, Cucchiaro J, Silva R, et al. Lurasidone monotherapy in the treatment of bipolar I depression: a randomized, double-blind, placebo-controlled study. Am J Psychiatry. 2014;171:160–168.
2. Loebel A, Cucchiaro J, Silva R, et al. Lurasidone as adjunctive therapy with lithium or valproate for the treatment of bipolar I depression: a randomized, double-blind, placebo-controlled study. Am J Psychiatry. 2014;171:169–177.

Lurasidone as Adjunctive Therapy With Lithium or Valproate for the Treatment of Bipolar I Depression: A Randomized, Double-Blind, Placebo-Controlled Study

Loebel A, Cucchiaro J, Silva R, Kroger H, Sarma K, Xu J, Calabrese J.

Am J Psychiatry. 2014;171:169-177.

Objective2

  • Evaluate the efficacy of LATUDA as adjunctive therapy with lithium or valproate for the treatment of bipolar I depression

Study design2

  • Patients who had not adequately responded to ≥28 days of lithium or valproate were randomized to receive 6 weeks of double-blind adjunctive treatment with LATUDA (n=183) or placebo (n=165) added to therapeutic levels of either lithium or valproate. At screening, serum levels for lithium and valproate were required to be 0.6­–1.2 mEq/L and 50–125 µg/mL, respectively.

Dosing2

  • Patients assigned to receive LATUDA underwent a fixed titration period for one week, before flexible dosing:
    • LATUDA 20 mg/day: Days 1 to 3
    • LATUDA 40 mg/day: Days 4 to 6
    • LATUDA 60 mg/day: Day 7
  • Flexible dosing of LATUDA within the dosing range of 20–120 mg/day was permitted after Day 7 in 20-mg increments/decrements
  • Mood stabilizer dose adjustments were permitted to maintain a serum level of 0.6–1.2 mEq/L for lithium or 50–125 µg/ml for valproate
  • LATUDA or placebo was taken once daily in the evening, with a meal or within 30 minutes after eating 

Endpoints2

  • Primary: Mean change from baseline to Week 6 in Montgomery-Åsberg Depression Rating Scale (MADRS) scores
  • Key secondary: Mean change from baseline to Week 6 in CGI-BP depression scores

Summary of results2

  • LATUDA 20–120 mg/day as adjunctive therapy with lithium or valproate significantly reduced mean MADRS total scores at Week 6 compared with placebo
  • LATUDA resulted in significantly greater reduction in CGI-BP depression scores at Week 6 compared with placebo
  • In the LATUDA and placebo groups, respectively, discontinuation rates due to adverse events were 6.0% and 7.9%
  • Minimal changes in weight, lipids, and glucose were observed during treatment with LATUDA

Download Overview


References:
1.
Loebel A, Cucchiaro J, Silva R, et al. Lurasidone monotherapy in the treatment of bipolar I depression: a randomized, double-blind, placebo-controlled study. Am J Psychiatry. 2014;171:160–168.
2. Loebel A, Cucchiaro J, Silva R, et al. Lurasidone as adjunctive therapy with lithium or valproate for the treatment of bipolar I depression: a randomized, double-blind, placebo-controlled study. Am J Psychiatry. 2014;171:169–177.

Important Safety Information & Indications

INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS; AND SUICIDAL THOUGHTS AND BEHAVIORS 

CONTRAINDICATIONS
LATUDA is contraindicated in the following:

WARNINGS AND PRECAUTIONS
Cerebrovascular Adverse Reactions, Including Stroke: In placebo-controlled trials with risperidone, aripiprazole, and olanzapine in elderly subjects with dementia, there was a higher incidence of cerebrovascular adverse reactions (cerebrovascular accidents and transient ischemic attacks) including fatalities compared to placebo-treated subjects. LATUDA is not approved for the treatment of patients with dementia-related psychosis.

Neuroleptic Malignant Syndrome (NMS): NMS, a potentially fatal symptom complex, has been reported with administration of antipsychotic drugs, including LATUDA. NMS can cause hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. Management should include immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, intensive symptomatic treatment and medical monitoring, and treatment of any concomitant serious medical problems.

Tardive Dyskinesia (TD): TD is a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements that can develop in patients with antipsychotic drugs. There is no known treatment for established cases of TD, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. The risk of developing TD and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses. Given these considerations, LATUDA should be prescribed in a manner that is most likely to minimize the occurrence of TD. If signs and symptoms appear in a patient on LATUDA, drug discontinuation should be considered.

Metabolic Changes

Hyperglycemia and Diabetes Mellitus: Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing.  In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug.

Dyslipidemia: Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.

Weight Gain: Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.

Hyperprolactinemia: As with other drugs that antagonize dopamine D2 receptors, LATUDA elevates prolactin levels.  Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds.

Adult patients with bipolar depression:

In the short-term, placebo-controlled monotherapy study, the median change from baseline to endpoint in prolactin levels for LATUDA-treated females was 3.1 ng/mL and was 1.5 ng/mL for males.  The proportion of female patients with prolactin elevations ≥5x ULN was 0.6% for LATUDA-treated patients versus 0% for placebo-treated female patients. The proportion of male patients with prolactin elevations ≥5x ULN was 0% for LATUDA-treated patients versus 0% for placebo-treated male patients.In the short-term, placebo-controlled adjunctive therapy with lithium or valproate study, the median change from baseline to endpoint in prolactin levels for LATUDA-treated females was 3.2 ng/mL and was 2.4 ng/mL for males. The proportion of female patients with prolactin elevations ≥5x ULN was 0% for LATUDA-treated patients versus 0% for placebo-treated female patients. The proportion of male patients with prolactin elevations ≥5x ULN was 0% for LATUDA-treated patients versus 0% for placebo-treated male patients.

Adult patients with schizophrenia:

In the short-term, placebo-controlled studies, the median change from baseline to endpoint in prolactin levels for LATUDA-treated females was -0.2 ng/mL and was 0.5 ng/mL for males. The proportion of female patients with prolactin elevations ≥5x ULN was 5.7% for LATUDA-treated patients versus 2.0% for placebo-treated female patients. The proportion of male patients with prolactin elevations ≥5x ULN was 1.6% for LATUDA-treated patients versus 0.6% for placebo-treated male patients.

Leukopenia, Neutropenia, and Agranulocytosis: Leukopenia/neutropenia has been reported during treatment with antipsychotic agents. Agranulocytosis (including fatal cases) has been reported with other agents in the class. Patients with a preexisting low white blood cell count (WBC) or a history of drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy, and LATUDA should be discontinued at the first sign of a decline in WBC in the absence of other causative factors.

Orthostatic Hypotension and Syncope: LATUDA may cause orthostatic hypotension. Orthostatic vital signs should be monitored in patients who are vulnerable to hypotension, in patients with known cardiovascular disease or history of cerebrovascular disease and in patients who are antipsychotic-naїve.

Seizures: LATUDA should be used cautiously in patients with a history of seizures or with conditions that lower seizure threshold (e.g., Alzheimer’s dementia).

Potential for Cognitive and Motor Impairment: Patients should be cautioned about operating hazardous machinery, including motor vehicles, until they are reasonably certain that therapy with LATUDA does not affect them adversely.

Body Temperature Regulation: Disruption of the body’s ability to reduce core body temperature has been attributed to antipsychotic agents.  Appropriate care is advised when prescribing LATUDA for patients who will be experiencing conditions that may contribute to an elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration.

Suicide: The possibility of suicide attempt is inherent in psychotic illness and close supervision of high-risk patients should accompany drug therapy. Prescriptions for LATUDA should be written for the smallest quantity of tablets consistent with good patient management in order to reduce the risk of overdose.

Dysphagia: Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in elderly patients, in particular those with advanced Alzheimer’s dementia. LATUDA and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.

ADVERSE REACTIONS
Commonly observed adverse reactions (≥5% incidence and at least twice the rate of placebo) for LATUDA:

Indications
LATUDA is indicated for:

Before prescribing LATUDA, please read the full Prescribing Information, including Boxed Warnings.