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