High Dose Lurasidone for Patients With Treatment Resistant Schizophrenia

The purpose of this study is to conduct a double-blind, randomized trial of lurasidone (80 mg vs 160-240 mg/day) after a 6 week trial of 80 mg/day (phase 1), in treatment resistant adult patients. Only those patients who still have persistent moderate to severe positive symptoms, even if they have shown some improvement at 80 mg/day will proceed to phase II (randomization). In phase II, 30 subjects will be randomized to continue 80 mg lurasidone and 40 will initiate a titration schedule, beginning at 120 mg at week 7. The high-dose group will be increased an additional 40 mg/day every week, thereafter, to a total of 240 mg/day, if adequately tolerated, which would include a worsening of psychopathology as assessed by the PANSS or CGI-S. The dose will remain at 240/day, or the highest dose tolerated, for a duration of 6 months from the time the 120 mg/day dose was initiated. No additional antipsychotic drug of any kind will be permitted in either group during Phase II. Because they are treatment resistant, patients who are doing poorly in either of the two groups in phase II as indicated by level of psychopathology, or as tolerated, and who the clinicians at any site feel should no longer receive lurasidone, will be dropped, and would ordinarily be considered for treatment with clozapine. Where possible, another assessment of these patients, two weeks and four weeks after completion of the trial or early termination will be conducted.

All subjects who enter the phase 1 study will be consented to obtain a blood sample for genetic studies to search for possible markers for response to lurasidone and treatment resistant schizophrenia. DNA from non-treatment resistant patients already studied by the PI will be available for comparison. Following the completion of the study, the PI and the sponsor will discuss how best to analyze the DNA obtained and a separate contract will be written, if indicated.

Inclusion criteria

• Patients diagnosed with schizophrenia or schizoaffective disorder according to Diagnostic and Statistical Manual IV (DSM-IV) criteria
• All patients must be capable of giving written informed consent.
• The criteria for treatment resistance (TR) will be those of Kane et al, (1988) which are:

• failure to respond adequately to two or more trials with typical or atypical antipsychotic drugs, of adequate dose and duration (at least 6 weeks) lifetime and at least one such trial within the last two years. No patient with a history of a successful trial of this nature within the last two years will be eligible for inclusion. The minimum doses of antipsychotic drugs permitted in these unsuccessful trials are specified in Table 1.
• Patients must have scores of 4 (using a 1-7 scale) or more on at least two of the following Positive and Negative Syndrome Scale (PANSS) items: delusions [P1], hallucinations [P3] or unusual thought content [G9]
• Patients must have a total PANSS score of 70 or above
• Patients will have had no episodes of good functioning in the previous three years (as defined by current CGI - Severity of moderate to severe, Global Assessment of Functioning (GAF) below 60;
• Personal and Social Performance Scale of 60 or below.
• Requirement for previous exposure to antipsychotic treatment:

Patients who meet treatment resistance criteria must have had at least two trials with approved antipsychotic drugs, typical or atypical, in the standard dose range. It is recognized that some treatment resistant patients will have had good responses to antipsychotic drugs before meeting treatment resistant criteria.

• All patients must have a Clinical Global Impression - Severity (CGI-S) scale score at screening of at least moderate severity, and must have a Personal and Social Performance (PSP) score of 60 or below.
• Patients may initially be inpatients or outpatients.
• Females of child bearing potential will be admitted only if they are on stable birth control medication and understand that they should not get pregnant during the course of the study. Pregnancy tests will be done at baseline and at approximately 2 month intervals.
• All patients must have stable housing at the current time or will be discharged to a stable outpatient setting for housing, if an inpatient.
• Patients must be willing to remain compliant on oral medication throughout the duration of the trial.

Exclusion criteria

• Patients unable to provide written, informed consent
• Patients with a diagnosis other than schizophrenia or schizoaffective disorder.
• Patients currently taking clozapine or have failed an adequate trial of clozapine which lasted at least 2 months.
• Patients who have already failed trials with high doses of other atypical antipsychotic drugs such as risperidone or olanzapine..
• Pregnant females and females who are currently breastfeeding will be excluded.
• Patients with a diagnosis of substance dependence at screening or up to one year prior to enrollment.
• Patients with a history of non-compliance to oral medication to a degree that would interfere with the determination of treatment resistance or diminish likelihood of complying with this protocol
• Patients > age 60
• Uncontrolled medical conditions or recent myocardial infarction or stroke
• BMI =/>45