Major Depressive DisorderPhase 4NCT05537584
SMART Trial to Predict Anhedonia Response to Antidepressant Treatment
A Phase 4 study testing Sertraline and Bupropion in people with Major Depressive Disorder, run by Mclean Hospital at 1 site in United States.
Trial summary
The main goal of this research is to use behavioral, brain, and clinical data to determine which type of antidepressant might be optimal before people with depression start treatment. Read more about this study
- Who is it for?
- Ages 18 to 64 years
- Conditions the study is for
- Major Depressive Disorder
- What is being tested?
- Sertraline and Bupropion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 57 participants
- Where
- 1 siteUnited States
- Study dates
- 30 Sep 2022to 26 Aug 2025
- Phase
- Phase 4
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 64 years
- All sexes
- No healthy volunteers
- Adult
Who may be able to join
- 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
Show all 9Show fewer
- 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
Who cannot join
- 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
Show all 34Show fewer
- 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:
- 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)
- 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)
- 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)
- Cocaine, meth/psychostimulants (this includes prescribed stimulants such as methylphenidate) exclude for 5 uses in the past year, or 10 uses lifetime
- Prescribed opioids for a limited period (e.g., post-surgery) is OK if no use in the past 3 months
- 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).
Trial locations and contacts
1 site in 1 country.
About this study
The main goal of this research is to use behavioral, brain, and clinical data to determine which type of antidepressant might be optimal before people with depression start treatment.
Read the detailed description
The treatment of depression is often trial-and-error. Earlier research reported that only 50% of individuals with depression show a significant decline in symptoms after taking an antidepressant. The situation is even worse in primary care, where only 30% respond to first line antidepressants.
The difficulty in treating depression is likely because treatment selection is not based on each person's characteristics. While some depressed individuals may benefit from selective serotonin reuptake inhibitors (SSRIs), others might benefit more from other types of medication. Finding markers that predict an individual's response to different antidepressants would provide patients and clinicians with valuable information to guide treatment selection.
The present study is among the first to use clinical (e.g., responses on questionnaires), behavioral (e.g., performance in computerized tasks), and brain (e.g., MRI scans) data to guide treatment selection in order to increase the likelihood of benefiting from one of two antidepressants. After analyzing an individuals' markers, subjects will be randomly assigned to receive a full 8-week course of an SSRI or non-SSRI.
Throughout the study, participants will complete 9 total sessions over the course of 9-10 weeks, including an electroencephalogram (EEG) recording, a functional magnetic resonance imaging (fMRI) scan, an electrocardiogram (EKG) exam, interviews with clinicians, and a full 8-week course of an antidepressant.
- Conditions
- Major Depressive Disorder
- Being tested
- Sertraline, Bupropion
- Medical subject headings
- Depressive Disorder, Major
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
SertralineDrug
Also called Zoloft
Subjects will receive 8 weeks of sertraline while monitored by the study physician
BupropionDrug
Also called Wellbutrin
Subjects will receive 8 weeks of bupropion while monitored by the study physician
| Study group | Role | What they receive |
|---|---|---|
| MDD with SERT+ Response Marker | Experimental | Participants with MDD who have been classified as high sertraline responders based on behavioral and brain data. Receives: Drug: Sertraline; Drug: Bupropion |
| MDD with BUP+ Response Marker | Experimental | Participants with MDD who have been classified as high bupropion responders based on behavioral and brain data. Receives: Drug: Sertraline; Drug: Bupropion |
What is being measured
The primary outcome is the main question the study is designed to answer.
Montgomery-Åsberg Depression Rating Scale (MADRS)
The Montgomery-Åsberg Depression Rating Scale (MADRS) - Clinician-Rated Scale measures depressive symptom severity and is administered by a trained clinician. The scale includes 10 items assessing symptoms such as sadness, inner tension, sleep, appetite, concentration, energy, anhedonia, pessimistic thoughts, and suicidal thoughts. Each item is rated from 0-6, with a total score range of 0-60, calculated by summing all item scores. Higher scores indicate greater depression severity (worse outcome), whereas lower scores indicate fewer depressive symptoms (better outcome).
Measured: Baseline and Week 8 of treatment/outcome assessment session
Secondary outcomes (5)
Ventral-striatal Activation During Reward Related Tasks in an fMRI Scan
Brain measure of anhedonia
Measured: 8-10 weeks
Effort-based Decision Making During an Effort-based Task
Behavioral measure of anhedonia
Measured: 8-10 weeks
Reward Positivity During a Guessing Monetary Reward Task
Behavioral measure of anhedonia
Measured: 8-10 weeks
Cortico-insular Activation During an Effort-based Task
Brain measure of anhedonia
Measured: 8-10 weeks
Resting State Functional Connectivity Between the NAc and mPFC During an fMRI Scan
Brain measure of anhedonia
Measured: 8-10 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 Sep 2022
- Study start30 Sep 2022
- Primary completion26 Aug 2025
- Study completion26 Aug 2025
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Major Depressive DisorderStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 57 participants (actual)
Sponsor and investigators
- Lead sponsor
- Mclean Hospital
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Diego Pizzagalli, Mclean Hospital
- Investigators
- Diego A. Pizzagalli, PhD, Principal investigator, Mclean Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05537584
- Sponsor's protocol ID
- 2022P000896
- Status last verified
- Oct 2026
- First submitted
- 6 Sep 2022
- Last updated
- 30 Oct 2026
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: We are part of a large team of researchers across the US called MCPsych which is funded through the Wellcome Leap Grant. We have a large repository of questionnaires, behavioral, and brain data that will be collected similar across sites and allow additional data analyses.
Study at a glance
From the registry record, last updated by the sponsor on 30 Oct 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- SMART Trial to Predict Anhedonia Response to Antidepressant Treatment
- ClinicalTrials.gov ID
- NCT05537584
- Acronym / sponsor ID
- 2022P000896
- Conditions
- Major Depressive Disorder
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 57 participants (actual)
- Lead sponsor
- Mclean HospitalUniversity, hospital or other
- Study start
- 30 Sep 2022 (actual)
- Primary completion
- 26 Aug 2025 (actual)
- Study completion
- 26 Aug 2025 (actual)
- First posted
- 13 Sep 2022 (actual)
- Results
- Posted 30 Oct 2026
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The main goal of this research is to use behavioral, brain, and clinical data to determine which type of antidepressant might be optimal before people with depression start treatment.
Detailed description
The treatment of depression is often trial-and-error. Earlier research reported that only 50% of individuals with depression show a significant decline in symptoms after taking an antidepressant. The situation is even worse in primary care, where only 30% respond to first line antidepressants.
The difficulty in treating depression is likely because treatment selection is not based on each person's characteristics. While some depressed individuals may benefit from selective serotonin reuptake inhibitors (SSRIs), others might benefit more from other types of medication. Finding markers that predict an individual's response to different antidepressants would provide patients and clinicians with valuable information to guide treatment selection.
The present study is among the first to use clinical (e.g., responses on questionnaires), behavioral (e.g., performance in computerized tasks), and brain (e.g., MRI scans) data to guide treatment selection in order to increase the likelihood of benefiting from one of two antidepressants. After analyzing an individuals' markers, subjects will be randomly assigned to receive a full 8-week course of an SSRI or non-SSRI.
Throughout the study, participants will complete 9 total sessions over the course of 9-10 weeks, including an electroencephalogram (EEG) recording, a functional magnetic resonance imaging (fMRI) scan, an electrocardiogram (EKG) exam, interviews with clinicians, and a full 8-week course of an antidepressant.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| MDD with SERT+ Response Marker | Experimental | Drug: Sertraline, Drug: BupropionParticipants with MDD who have been classified as high sertraline responders based on behavioral and brain data. |
| MDD with BUP+ Response Marker | Experimental | Drug: Sertraline, Drug: BupropionParticipants with MDD who have been classified as high bupropion responders based on behavioral and brain data. |
Who may qualify
- Ages
- 18 to 64 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (9 listed)
- 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
Key exclusion criteria (34 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| SertralineAlso: ZoloftSubjects will receive 8 weeks of sertraline while monitored by the study physician | Drug | MDD with BUP+ Response Marker, MDD with SERT+ Response Marker |
| BupropionAlso: WellbutrinSubjects will receive 8 weeks of bupropion while monitored by the study physician | Drug | MDD with BUP+ Response Marker, MDD with SERT+ Response Marker |
Primary outcome
Montgomery-Åsberg Depression Rating Scale (MADRS)
Time frame: Baseline and Week 8 of treatment/outcome assessment session
The Montgomery-Åsberg Depression Rating Scale (MADRS) - Clinician-Rated Scale measures depressive symptom severity and is administered by a trained clinician. The scale includes 10 items assessing symptoms such as sadness, inner tension, sleep, appetite, concentration, energy, anhedonia, pessimistic thoughts, and suicidal thoughts. Each item is rated from 0-6, with a total score range of 0-60, calculated by summing all item scores. Higher scores indicate greater depression severity (worse outcome), whereas lower scores indicate fewer depressive symptoms (better outcome).
5 secondary outcomes
Ventral-striatal Activation During Reward Related Tasks in an fMRI Scan
Time frame: 8-10 weeks
Effort-based Decision Making During an Effort-based Task
Time frame: 8-10 weeks
Reward Positivity During a Guessing Monetary Reward Task
Time frame: 8-10 weeks
Cortico-insular Activation During an Effort-based Task
Time frame: 8-10 weeks
Resting State Functional Connectivity Between the NAc and mPFC During an fMRI Scan
Time frame: 8-10 weeks
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 30 Oct 2026.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: Yes. We are part of a large team of researchers across the US called MCPsych which is funded through the Wellcome Leap Grant. We have a large repository of questionnaires, behavioral, and brain data that will be collected similar across sites and allow additional data analyses.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Diego A. Pizzagalli, PhD principal investigator
Mclean Hospital
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Sertraline and Bupropion in people with Major Depressive Disorder, run by Mclean Hospital at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 9 inclusion and 34 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 30 Oct 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 30 Oct 2026). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Montgomery-Åsberg Depression Rating Scale (MADRS) (time frame: Baseline and Week 8 of treatment/outcome assessment session). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 30 Oct 2026.