12-week Comparative Effectiveness Trial of Lamotrigine vs. Fluoxetine for Bipolar Depression

Condition(s) targeted: Bipolar Disorder

Intervention: Lamotrigine (Drug); Fluoxetine (Drug)

Phase: Phase 4

Status: Recruiting

Sponsored by: Mayo Clinic

Overall contact:
Scott Feeder, MS, Email: feeder.scott@mayo.edu

The FLAME Study is a 12-week, open randomized comparative effectiveness trial evaluating genomic predictors and biomarkers of response and adverse events to treatment with lamotrigine (n=300) and fluoxetine (n=300) for bipolar I, II and schizoaffective bipolar depressed participants. Participants age 18-85; will be invited to take part of this study. The study will last for 12-weeks with 6 study visits to here at Mayo Clinic Rochester. If after the 12-weeks patient does not respond to the medication there will be an option to cross over to the other medication (either Lamotrigine or Fluoxetine)

Official title: 12-week Open Randomized Comparative Effectiveness Trial of Lamotrigine vs. Fluoxetine for Bipolar Depression: Pharmacogenomic and Biomarker Predictors of Response

Study design: Allocation: Randomized, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: Inventory for Depressive Symptoms

Detailed description: Depression is the predominant prevailing mood state of bipolar disorder and it is associated with substantial morbidity and mortality. However, in comparison to acute mania, bipolar depression is understudied both from the standpoint of its pathophysiology as well as clinical trials and treatment development. Given the lack of evidence-based guidelines, clinicians and participants enter a treatment phase with little guidance. The FLAME Study is a 12-week, open randomized comparative effectiveness trial evaluating genomic predictors and biomarkers of response and adverse events to treatment with lamotrigine (n=300) and fluoxetine (n=300) for bipolar I, II and schizoaffective bipolar depressed participants. Participants age 18-85; will be invited to take part of this study. It is known that functionally significant genetic polymorphisms of pharmacokinetics and pharmacodynamic pathways can influence individual differences in repose to specific medications. We propose to evaluate the contribution of these pharmacogenomic variations to lamotrigine and fluoxetine treatment response and adverse events. We will correlate clinical phenotypes of response and adverse events to treatment with genotype and haplotype variations of drug metabolism, neurotransmitter biosynthesis, (metabolism, storage, release, reuptake), receptor and intracellular signaling-that have been previously implicated to either lamotrigine or fluoxetine. These initial steps will be complemented with genome-wide analysis (GWA), pathway analysis and other candidate gene studies. Based on our results we aim to develop a translational treatment algorithm of bipolar depression that may help individualized treatment for bipolar depression. This algorithm for participants could potentially increase the likelihood of successful treatment interventions, deliver the "right treatment, for the right participant at the right time", and decrease the number of ineffective treatments and/or risk for serious adverse events.

Minimum age: 18 Years. Maximum age: 85 Years. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Adult participants, age 18-85.

- Outpatients or inpatients with a diagnosis of bipolar I, II or schizoaffective

bipolar disorder, depressed phase, non-psychotic, (DSM-5 criteria, Structured Clinical Interview for the Diagnostic and Statistical Manual for Mental Disorders Module D confirmed) non-actively suicidal (Columbia-Suicide Severity Rating Scale C-SSRS (Posner et al. 2008) confirmed, see exclusion criteria below).

- At least mild symptoms of depression as defined by Inventory for Depressive Symptoms

(IDS; Rush et al., 1986) score of ≥14 and Clinical Global Impression for bipolar disorder (CGI-BP, Spearing et al. 1997) current severity of 3 (mild). Will this be an inclusion prior to blood draw?

- Bipolar I participants must be on conventional mood stabilizing treatment [lithium,

carbamazepine, oxcarbazepine, divalproate or atypical antipsychotic]. Participants with a bipolar II may pursue the FLAME Study as monotherapy. Participants with Bipolar Schizoaffective Disorder must be on an antipsychotic.

- Participants who are not planning pregnancy in the near future (3 months).

- Negative urine toxicology screen (except cannabis).

- Negative urine pregnancy test.

- No evidence of clinically significant laboratory screening tests (complete blood

count (CBC); electrolytes; thyroid stimulating hormone (TSH); creatinine/BUN, AST/ALT). Exclusion Criteria:

- Inability or unwilling to provide informed consent.

- Inability to understand English.

- Actively suicidal participants at screening or enrollment visit as defined by

screening questions from the C-SSRS, outlined as: "Yes" response to questions 4 or 5 or "Yes" response to questions 1, 2 or 3 with significant intensity level endorsed as score of 4 or higher at intensity of ideation section..

- Unwilling or unable to taper any antidepressant therapy.

- Substance Use Disorder within the last 3 months (caffeine,nicotine, and cannabis

excluded)

- Evidence of treatment resistance to medication for the duration of 1 month (40mg for

of fluoxetine or 200 mg of lamotrigine)

- Axis I or II comorbidity that by referring mental health professional and/or study

psychiatrist is primary need of treatment (This will be assessed by the site principal investigator, who has >10 years clinical experience with this population. Hospital discharge summaries and outpatient medical records may be reviewed (i. e. adequate trials of mood stabilizing treatments with minimal to no response, prominent self-injurious behavior in the absence of significant mood symptomatology, or atypical cycle patterns) to make this decision.

- Pregnant participants will be excluded.

- Participants who are currently breastfeeding and continue breastfeeding will be

excluded.

- Female not practicing a reliable form of birth control (condom, IUD, depo injection)

- Due to lamotrigine pharmacokinetics female wishing to commence oral contraceptive

therapy (OCT) within 3 months of enrollment date or anticipate discontinuing OCT during study (stable oral contraceptive therapy exception).

Scott Feeder, MS, Email: feeder.scott@mayo.edu

Mayo Clinic, Rochester, Minnesota 55905, United States; Recruiting
Scott Feeder, Email: feeder.scott@mayo.edu

Starting date: March 2015
Last updated: March 16, 2015