SMART Trial to Predict Anhedonia Response to Antidepressant Treatment

Inclusion Criteria: * Ages 18 to 64 * Any gender and all ethnic/racial origins * Diagnosis of Major Depressive Disorder. MDD diagnosis will be decided by clinicians via the Structured Clinical Interview for DSM-5 (SCID-5). * Elevated depression severity * Elevated anhedonia symptoms * Fluency in written and spoken English * Ability to give signed, informed consent either written or electronic * Normal or corrected-to-normal vision and hearing * Ability to adhere to the study schedule Exclusion Criteria: * Patient is currently enrolled in any treatment program except psychotherapy (transcranial magnetic stimulation, other antidepressants etc.). * Any contraindication to bupropion or sertraline considered unsafe by the study physician, or any history of adverse reaction to either drug. * Failure to respond to an adequate course of treatment with both of the study medications (sertraline or bupropion) during the current episode. * Participants who are determined to be treatment resistant, (i.e., having failed to respond to at least two adequate antidepressant trials in the current episode) * Pregnant women, or women of childbearing potential who have a positive result on a urine pregnancy test * Failure to meet MRI safety requirements, including any metal implants or prostheses that cannot be removed, or exposure to shrapnel * Claustrophobia or severe anxiety that might affect participation in neuroimaging * Injury or movement disorder that may make it difficult to lie still in the scanner * Any current recreational/illicit drug use, with the exception of THC, as assessed by a urine drug test (covering cocaine, cannabinoids, opiates, amphetamines, methamphetamines, phencyclidine, MDMA, benzodiazepines, methadone, oxycodone, tricyclic antidepressants, and barbiturates). Participants who use THC regularly will be allowed to continue in the study provided they have abstained for the three days prior to visits involving the MRI scan. * Use of Monoamine Oxidase Inhibitors (MAOIs) either currently or within the past two weeks * Participants who are currently stopping the use of tobacco products. Participants who cannot abstain from tobacco products for eight hours without cravings. * More than 15 alcohol-induced lifetime blackouts. * History of regular use (5-7xs per week) of marijuana before the age of 15 * Lifetime history of other recreational drug use beyond the following limits (for each drug individually) and/or last use within the past 3 months: 1. Hallucinogens (mushrooms, LSD): exclude for12 uses in the past year, or 15 uses lifetime (unless last use was 5+ years ago, then allow up to 25 lifetime uses) 2. Ecstasy: exclude for 12 uses in the past year, or 15 uses lifetime (unless last use was 5+ years ago, then allow up to 25 lifetime uses) 3. Anxiolytics (recreational use): exclude for 12 uses in the past year, or 15 uses life time (unless last use was 5+ years ago, then allow up to 25 lifetime uses) 4. Cocaine, meth/psychostimulants (this includes prescribed stimulants such as methylphenidate) exclude for 5 uses in the past year, or 10 uses lifetime 5. Prescribed opioids for a limited period (e.g., post-surgery) is OK if no use in the past 3 months 6. 3 uses: Inhalants, IV drugs, crack cocaine, or crystal methamphetamine * Recent use (within 3 weeks) of any medication that affects blood flow or blood pressure, or which is vasodilating/vasoconstricting (for participants undergoing neuroimaging) * Metformin use in the past 6 months (for either clinical care or as part of research) * Serious or unstable medical illness * Current infectious illness (either transient or chronic); Current episode of allergic reaction or asthma * Hemophilia; Diabetes with poor glucose control; History of chronic migraine (\> 15 days/mo.); History of dementia. * History of seizures or seizure disorder. * Any history of significant head injury or concussion with loss of consciousness for two minutes or more, or head injury with lingering functional/psychological impact * Serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or other serious cardiac problems (contraindication to bupropion)- confirmed with ECG at physicians' discretion. * Past/current DSM-5 diagnosis of: OCD, schizophrenia or other psychotic disorders, schizoaffective disorder, delusional disorder, psychotic disorders NOS, bipolar disorder, patients with mood congruent or mood incongruent psychotic features, autism or any other pervasive developmental disorder, organic mental disorder, PTSD (current only), somatoform disorder, severe borderline or antisocial personality disorder, anorexia or current subthreshold anorexia, binge eating disorder, or bulimia (however bulimia is allowed if it has been fully remitted in the past 2 years; binge eating disorder is allowable if it has been partially remitted within the past 3 months; current subthreshold binge eating disorder is allowable; past PTSD fully remitted for longer than one month and current partial remission of PTSD is allowable) * Current mild, moderate, or severe substance (including cannabis) or alcohol use disorder. Early or sustained remission is allowable, i.e., criteria for any level of abuse has not been met for at least the past 3 months (with the exception of past or current cocaine, stimulant, or opioid abuse, which will lead to automatic exclusion). * Specific phobia, social anxiety disorder and generalized anxiety disorders will be allowed only if judged to be currently mild and never the principal diagnosis when co-occurring with current or past MDD. Panic disorder will be allowed if MDD is the principal diagnosis and panic disorder has been in remission for \> 2 years. * Electroconvulsive Therapy in the current episode. * Patient is clinically unstable, in the judgment of the clinician or physician. * Participants with suicidal ideation where continued study participation is believed unsafe by the study clinician or study physician (these participants will be immediately referred to appropriate clinical treatment).