Inclusion Criteria:

• Adults between 18 and 65 years of age.
• Bipolar I or II disorder as confirmed by structured clinical interview for DSM-IV-TR.
• Major depressive episode unresponsive to steady and stable (i.e., at least 2 weeks) mood stabilization (e.g., lithium, valproate, lamotrigine, carbamazepine/oxcarbamazepine, and/or atypical antipsychotic therapy) and non-psychotropic medication.
• Antidepressant therapy is allowed in the study as long as patients are also on a mood stabilizer. Patients will be enrolled provided that any needed modifications to the antidepressant would be made at least two weeks prior to randomization.
• Patients receiving psychotherapy will be allowed to be randomized provided therapy frequency does not change during the 8-week blinded phase.  
• Symptom severity score on the Quick Inventory for Depressive Symptomatology – Clinician (QIDS-C16) ≥ 9, and the Clinical Global Impression for Bipolar Illness (CGI-BP) Depression Severity Scale ≥ 3.
• Patients on stimulants for comorbid attention deficit disorder (ADHD) and/or binge eating disorder (BED) will be enrolled provided that the stimulant can be tapered and discontinued at least one week prior to randomization; symptom severity inclusion criteria must be met again prior to randomization.
• Patients with a prescribed opiate (e.g.. hydroxicodone) or other pain intervention for acute or chronic pain management will be allowed provided they:
  • use a prescribed opiate or other pain intervention at a recommendation dose and established duration;
  • show no evidence of prescription misuse;
  • do not meet abuse or dependence criteria by SCID;
  • no known significant pharmacological interactions.
• Ability to travel for the assessment visits.  

Exclusion Criteria:

• Inability to provide written informed consent.
• Inability to understand English.
• Score less than 86% correct (i.e., one wrong) on comprehension assessment that reviews study goals.
• Clinically significant signs of acute suicidality from any of the following assessments:
  • Response of > 2 on question #12 of QIDS-C; or
  •  Response = 3 on the SCID Module A- #A19.
• Suicide attempt within the past year.
• Concomitant treatment with monoamine oxidase inhibitors (MAOIs); also, within 14 days following discontinuation of treatment with a monoamine oxidase inhibitor.
• Baseline Young Mania Rating Scale (YMRS) score ≥ 12.
• Patients with active psychosis (measured by a score > 4 on YMRS question #8) or a diagnosis of schizophrenia, schizoaffective disorder, delusional, or schizophreniform disorder identified by structured clinical interview for DSM-IV-TR.
• Active abuse or dependence of alcohol, opiates, or cannabis (nicotine dependence will be an exception) by structured clinical interview for DSM-IV-TR; patients meeting full remission for at least 3 months can be randomized. 
• Positive toxicology screen for drugs of abuse (i.e., cocaine, methamphetamine, illegal opiates).
• Positive toxicology screen for cannabis and a cannabis use disorder by structured clinical interview for DSM-IV-TR.  Participants who use cannabis for recreational or medicinal purposes and fail the toxicology screen can potentially be included in the study only if they take the CUDIT-R and score a 12 or less.
• Known lifetime history of cocaine or methamphetamine abuse or dependence identified by structured clinical interview for DSM-IV-TR.
• Active stimulant prescription abuse or dependence by structured clinical interview for DSM-IV-TR; patients meeting full remission for at least 6 months can be randomized.
• Known lifetime history of stimulant-induced mania.
• Known hypersensitivity, such as angioedema or anaphylaxis, to amphetamines or other ingredients of MYDAYIS.
• Clinically unstable medical disease.
• Known history of a structural cardiac abnormality, cardiomyopathy, serious heart rhythm abnormality, coronary artery disease, stroke, or other serious cardiovascular problems.
• ECG with clinically significant arrhythmias, conduction abnormalities, or voltage criteria met for left ventricular hypertrophy (unless cleared by cardiology consultation).
• Uncontrolled hypertension (> 160/100) or tachycardia (heart rate > 110).
• History of grand mal seizure; history of febrile seizure as infant permitted.
• Established vasculopathy or history of Raynaud’s phenomena.
• Narrow angle glaucoma.
• Chronic kidney disease (CKD) > stage IIIa (GFR 40-59).
• Tourette syndrome.
• Women who are pregnant, lactating or of child-bearing potential not using at least one adequate contraceptive measure (i.e., hormonal contraception-birth control pills, intrauterine devices (IUD), tubal ligation or condoms during sexual intercourse).
• Current positive test for SARS-CoV-2; those with previous COVID-19 illness and those who test positive for SARS-CoV-2 any time after starting study drug or placebo will be included.
• Otherwise excluded for administrative reasons and/or clinician judgment.

Eligibility last updated 3/22/22. Questions regarding updates should be directed to the study team contact.