Quetiapine XR for Cognitive and Functional Disability in Clinically Stable Patients With Bipolar Disorder

Phase IV Study of Quetiapine XR Aimed at Disability and Cognitive Impairments.

Quetiapine has been reported to have beneficial cognitive effects in several randomized controlled trials in schizophrenia. It has not yet been studied in bipolar disorder, but promising results from the use of extended release quetiapine for the maintenance treatment of bipolar disorder suggests that its cognitive benefits could be detected. Moreover, quetiapine has been shown to have direct beneficial effects on performance-based measures of social competence in schizophrenia and to improve quality of life (QoL) in bipolar depression. The investigators propose to study quetiapine augmentation of mood stabilizer monotherapy in clinically stable patients with bipolar disorder. This will be a randomized, placebo controlled trial, with attentional impairments as the primary outcome and other cognitive performance variables and measures of social and everyday living skills, as well as subjective QoL, as the secondary outcomes.

In contrast to previous conceptions of bipolar disorder as an illness where cognitive impairments were limited to manic and depressed episodes, it has become clear that cognitive impairments are common in clinically stable bipolar patients.

Quetiapine has been reported to have beneficial cognitive effects in several randomized controlled trials in schizophrenia. It has not yet been studied in bipolar disorder, but promising results from the use of extended release quetiapine for the maintenance treatment of bipolar disorder suggests that its cognitive benefits could be detected. Moreover, quetiapine has been shown to have direct beneficial effects on performance-based measures of social competence in schizophrenia and to improve quality of life (QoL) in bipolar depression. We propose to study quetiapine augmentation of mood stabilizer monotherapy in clinically stable patients with bipolar disorder. This will be a randomized, placebo controlled trial, with attentional impairments as the primary outcome and other cognitive performance variables and measures of social and everyday living skills, as well as subjective QoL, as the secondary outcomes.

An additional possible benefit of quetiapine treatment, and one that is directly relevant to neuropsychological performance, is that of increased activity of cortical norepinephrine (NE). Thus, in studies of cognitive enhancement with quetiapine, examination of cortical NE neet occupancy will be of substantial interest.

General Background: This will be a three site study which will include Emory University (Coordinating site), Duke University, and University of Toronto. We choose to have three sites so that the difficult task of recruiting clinically stable patients with bipolar can be accomplished quickly and the study can be completed within a two-year time frame.

Subjects: We will recruit 100 patients for this study. Fifty percent of them will receive active treatment with quetiapine XR. All participants will meet diagnostic criteria for bipolar I and II disorder and have medical record-based evidence of at least one previous manic or mixed episode. They will be clinically stable, as evidence by meeting criteria for low scores on both the Young Mania Rating Scale (YMRS) and the Montgomery-Asberg Depression rating scale (MADRS). They will also be receiving therapy with mood stabilizers, either lithium or an approved mood stabilizing agent.

Visit Schedule: This is a 10 week study with a six-week active treatment protocol. All interested patients who meet study entry criteria will be screened for stability four and two weeks prior to the baseline assessment. Patients will also be re-assessed for stability at baseline. Patients who fail to meet entry criteria at baseline can come back for a second screening after 2 and 4 weeks.

Throughout treatment, medication adjustments will be limited to changes of less than 25% during this time period.

Assessments: Cognitive assessments will be performed at baseline, week 2 and week 6 of active treatment.

Clinical Assessments will be performed at screening and rescreening, baseline, weeks 2 and 6.

Biological Measures: Bloods for NE net occupancy will be drawn at baseline, week 2, and week 6. Serum levels of quetiapine at all three assessments will also be examined.

Cognitive Assessments:

We will focus our cognitive assessment on the types of cognitive impairments previously reported in bipolar disorder. Our focus will be on attention, episodic memory, processing speed, and working memory. This same instrumentation has proven able to detect sedation as well, so that we can use the results of our assessment to identify any potential adverse sedation effects.

Inclusion criteria:

1. Provision of written informed consent
2. A primary diagnosis of Bipolar disorder type 1 or 2, with a definite history of manic or hypomanic episodes by Diagnostic and Statistical Manual of Mental Disorders- Fourth Edition (DSM-IV).
3. Females and/or males aged 18-65 years.
4. Female patients of childbearing potential must be using a reliable method of contraception and have a negative urine human chorionic gonadotropin (HCG) test at enrolment.
5. Able to understand and comply with the requirements of the study.
6. YMDRS score <13.
7. MADRS score <19.
8. Currently receiving medication therapy with lithium, valproate, or lamotrigine or any combination thereof. (preference given to lithium and/or valproate).
9. Clinically stable for 4 weeks prior to study entry, confirmed at week 2.

Exclusion criteria:

1. Intolerance of quetiapine

2. Change in mood stabilizer medication or dose in the last 4 weeks, change in antidepressant medication or dose in the last two months.

3. Current treatment with carbamazepine, stimulants, atomoxetine, or another antipsychotic

4. Current treatment with norepinephrine reuptake inhibiting antidepressants (Milnacipran, bupropion, paroxetine, duloxetine, venlafaxine, all MAOI's, all TCAs)

5. Current pregnancy or lactation

6. Active Anorexia nervosa or Bulimia nervosa in the past six months

7. History of non-affective psychotic disorders (including schizoaffective disorder)

8. Patients who, in the opinion of the investigator, pose an imminent risk of suicide or a danger to self or others

9. Use of any of the following cytochrome P450 3A4 inhibitors in the 14 days preceding enrolment including but not limited to: ketoconazole, itraconazole, fluconazole, erythromycin, clarithromycin, troleandomycin, indinavir, nelfinavir, ritonavir, fluvoxamine and saquinavir

10. Use of any of the following cytochrome P450 inducers in the 14 days preceding enrollment including but not limited to: phenytoin, carbamazepine, barbiturates, rifampin, St. John's Wort, and glucocorticoids

11. Administration of a depot antipsychotic injection within one dosing interval (for the depot) before randomisation

12. Active Substance/ alcohol abuse or dependence in the past three months before enrollment ( except for caffeine or nicotine dependence), as defined by DSM-IV criteria Medical conditions that would affect absorption, distribution, metabolism, or excretion of study treatment

13. Unstable or inadequately treated medical illness (e.g. diabetes, angina pectoris, hyperlipidemia, hypertension) as judged by the investigator

14. Involvement in the planning and conduct of the study

15. Previous enrolment or randomisation of treatment in the present study.

16. Participation in another drug trial within 4 weeks prior enrolment into this study or longer in accordance with local requirements

17. A patient with Diabetes Mellitus (DM) fulfilling one of the following criteria:

    • Unstable DM defined as enrollment glycosylated hemoglobin (HbA1c) >8.5%.
    • Admitted to hospital for treatment of DM or DM related illness in past 12 weeks.
    • Not under physician care for DM
    • Physician responsible for patient's DM care has not indicated that patient's DM is controlled.
    • Physician responsible for patient's DM care has not approved patient's participation in the study
    • Has not been on the same dose of oral hypoglycaemic drug(s) and/or diet for the 4 weeks prior to randomization. For thiazolidinediones (glitazones) this period should not be less than 8 Weeks.
    • Taking insulin whose daily dose on one occasion in the past 4 weeks has been more than 10% above or below their mean dose in the preceding 4 weeks Note: If a diabetic patient meets one of these criteria, the patient is to be excluded even if the treating physician believes that the patient is stable and can participate in the study.

18. An absolute neutrophil count (ANC) of < 1.5 x 10^9 per liter