Cognitive Strategies in Early Psychosis 2 – how brain games and pills test decision making

Inclusion Criteria:

* Between the ages of 18 and 35
* Onset of a psychosis spectrum illness (schizophrenia, schizoaffective disorder, schizophreniform disorder, psychosis NOS, bipolar disorder with psychosis, or major depressive disorder with psychosis) within 5 years of enrollment
* Estimated IQ of 70 or above
* Proficient at English as determined through interactions with the study team
* No change in psychiatric medication within a week of enrollment or MRI study visits
* No clinically significant change in any medications for at least 1 month prior to study participation or MRI study visits, as determined by PI/Co-Is

  * Participants may have minor adjustments in medication doses in the past 30 days, per PI discretion, but may not have had major increases or decreases in doses, or additions or removal of medication within the past 30 days.
  * Participants are to have no changes to medications in the past 7 days before drug administration (i.e., must have been on a stable dose for at least 7 days prior to receiving the study drug).

Exclusion Criteria:

Medical Criteria:

* Presence of the following medical concerns as determined by the study PI:

  * Major neurological disorder
  * History of a clinically significant head injury with or without prolonged unconsciousness
  * Any major medical condition that, in the opinion of the PI, would impede participation in the study or would put the participant at additional risk by participating
* History of any of the following as reported by the participant:

  * Renal impairment, injury, or disease
  * Hepatic impairment, injury, or disease
  * Myocardial infarction or heart disease, or endorsement of history of or of cardiac symptoms at intake:

    * Dyspnea
    * Palpitations
    * Orthopnea
    * Pedal oedema
    * Significant dizziness
    * Syncope
    * Claudication
  * Low white blood cell count, or is diagnosed with leukopenia, neutropenia, or agranulocytosis
* Presence of unmanaged hypertension (\>140/90) or elevated resting heart rate (\>100 bpm)
* Abnormal clinical laboratory values:

  * uACR \> 30 mg/g
  * creatinine level \>0.95 mg/dL
  * AST or ALT \> 50 U/L
  * Bilirubin \> 1.2 mg/dL
  * Total Protein \< 6 g/dL
* Taking a medication or supplement that has a major drug interaction with any study drugs (e.g., ketamine, MAOIs, clomipramine, diazepam, propranolol, warfarin)
* Allergies to study drugs
* Is pregnant, planning to become pregnant, or is breastfeeding
* Cannot pass the visual acuity test
* Cannot pass the CMRR Subject Safety Screen due to MRI contraindications

Mental health criteria:

* Meets criteria for a severe substance or alcohol use disorder within 3 months of enrollment
* Lifetime history of a stimulant use disorder
* Current manic episode as determined by the MINI
* History of psychiatric hospitalization within 3 months of enrollment
* Meets criteria for clinical risk of suicidal behavior, as defined by:

  * Clinician judgment
  * A suicide attempt within 3 months of enrollment
  * Active suicidal ideation at screening or baseline, as indicated by the C-SSRS Screener
  * Previous intent to act on suicidal ideation with a specific plan and/or preparatory acts within 3 months of enrollment, as indicated by the C-SSRS Screener
* Symptom severity scores in the severe (6) or extremely severe (7) range on the BPRS for the following items: suicidality, disorientation, bizarre behavior, excitement, elevated mood
* Any other psychiatric symptoms or conditions that, in the opinion of the PI, would impede participation in the study or put the participant at additional risk by participating

Other criteria:

* Unable or unwilling to provide informed consent
* Unable to demonstrate adequate decisional capacity, in the judgment of the consenting study staff member, to make a choice about participating in the research study
* Current guardianship
* Is under civil commitment or under a stay of civil commitment
* Illiteracy
* Has engaged in significant cognitive training, in the opinion of the PI, in the last year