Intervention: Lamotrigine
Trial phase: Phase 4
ATC code: N03AX09
SMILES: Nc1nnc(-c2cccc(Cl)c2Cl)c(N)n1
Sex: All
Age groups: Adult | Older Adult
Healthy volunteers: No
Participants at risk: 2
Group description: Subjects on this arm will be randomized to Lamotrigine.

Lamotrigine: Lamotrigine dosing: 25 mg daily x 2 weeks, 50 mg daily x 2 weeks, 100 mg daily x 2 weeks, 200 mg (100 mg bid)) x 4 weeks. If patient still has at least mild depressive symptoms, the dose can be increased to 300 mg daily for 2 weeks and 400 mg for 4 weeks. Dose will be held for treatment response and can be reduced for side effects.
Eligibility criteria:
Inclusion Criteria:

Adult participants, age 18-65.
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)
At least mild symptom severity of depression as defined by the Clinical Global Impression for Bipolar Disorder (CGI-BP, Spearing et al. 1997) >2.
Bipolar I participants must be on conventional mood stabilizing treatment [lithium, divalproex or valproate, or an atypical antipsychotic]. Participants with a bipolar II disorder may pursue the FLAME Study as monotherapy.
Negative urine pregnancy test.
Participants not planning pregnancy in the near future (6 months).
Negative urine toxicology screen (except cannabis).
No evidence of clinically significant laboratory screening tests (complete blood count (CBC); electrolytes; thyroid stimulating hormone (TSH); creatinine/blood urea nitrogen, Aspartate Aminotransferase (AST)/ALT). Clinical laboratory evaluation within the last three months is acceptable.

Exclusion Criteria:

Inability or unwilling to provide informed consent.
Inability to understand English.
Actively suicidal participants at screening or enrollment visit as defined by a response of 3 or 4 on question 4 of the Bipolar Inventory of Symptoms Scale (BISS).
Active delusions or hallucinations defined as a score of 3 or 4 on the BISS question 40 (persecutory ideas) or 41 (delusions or hallucinations).
Impaired insight as defined as a score of 3 or 4 on BISS question 42 (insight).
Hypomania defined by a BISS manic subscore of ≥15.
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
Unwilling or unable to taper any current antidepressant therapy
Participants currently breastfeeding
Female not practicing a reliable form of birth control (condom, intrauterine device (IUD), Depo-Provera injection)
Due to lamotrigine pharmacokinetics, female subjects wishing to commence oral contraceptive therapy (OCT) within 3 months of enrollment date or anticipate discontinuing OCT during study (stable oral contraceptive therapy exception).
History of active substance abuse disorder within the last 3 months (other than caffeine or cannabis)
Participants with medical contraindications that preclude lamotrigine or fluoxetine treatment
History of severe adverse reaction to lamotrigine and/or fluoxetine
Current carbamazepine or oxcarbazepine treatment
Unstable active medical illness