Fluoxetine Treatment of Depression in Down Syndrome

Inclusion Criteria:

1. Age 18-45 years.

2. Diagnosis of DS confirmed via genetic testing or a clinical diagnosis made by aclinician with significant experience treating patients with DS.

3. Diagnosis of major depressive disorder based on Diagnostic and Statistical Manual ofMental Disorders, Fifth Edition (DSM-5) criteria, confirmed through the StructuredClinical Interview for DSM-5 (SCID-5).

4. Moderately severe depression as evidenced by a Montgomery-Asberg Depression RatingScale (MADRS) score of 20 or greater at Screen and Baseline. A severity score on theMADRS was chosen as an inclusion criterion since it has been demonstrated to besensitive to change in adults with MDD.

5. A Clinical Global Impression Severity Item score > 4 (moderate) for depressionsymptoms at Screen and Baseline.

Exclusion Criteria:

1. Active primary diagnosis of obsessive-compulsive disorder, posttraumatic stressdisorder, bipolar disorder, psychosis, or substance use disorder. These disordersare exclusionary since the primary treatment of these disorders may require acutepsychosocial or medication treatments that would confound the assessments used inthis study. We will evaluate for these disorders using the corresponding SCID-5modules.

2. Current or previous diagnosis of dementia, or use of medication to treat dementia.Given the potential overlap between depression and dementia symptoms, we want toensure we are administering fluoxetine to patients with a diagnosis of depression.

3. Presence of any past or present conditions that would make treatment with fluoxetineunsafe. This includes allergy to fluoxetine, liver or kidney disease, unstable heartdisease, and/or pregnancy (or being sexually active without using acceptable methodsto prevent pregnancy).

4. Use of selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrinereuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), monoamine oxidaseinhibitors (MAOIs), bupropion, mirtazapine, antipsychotics, lithium, valproic acid,or carbamazepine. Subjects will need to be off these classes of medications for atleast 5 elimination half-lives prior to beginning the trial.

5. Use of other psychotropic medications which are ineffective, poorly tolerated, orsub-optimal in terms of dose. A board-certified psychiatrist will assess any otherpsychotropic medications being used and determine whether they are effective,tolerated, and optimal in terms of dose. If medications are ineffective, poorlytolerated, or sub-optimal in terms of dose, the study psychiatrist will work withthe subject and his/her treatment team to either taper or optimize the dose ofpsychotropic medications prior to study enrollment. Concurrent use of a psychotropicmedication (other than SSRIs, SNRIs, TCAs, MAOIs, bupropion, mirtazapine,antipsychotics, lithium, valproic acid, or carbamazepine) will be allowed if thedose has been stable for 30 days and if they meet the criteria of effectiveness,tolerability, and dose.

6. Previous adequate trial of fluoxetine. An adequate trial will be defined as a totaldaily dose of ≥30 mg for at least 4 weeks. In addition, subjects who developedsignificant adverse effects during a trial of fluoxetine at any dose or durationwill be excluded.

7. Severe or profound intellectual disability based on clinical assessment and reviewof standardized assessment of cognitive skills. Participants determined to havesevere or profound intellectual disability will be excluded.

8. Use of medications that pose a clinically significant risk of a drug-druginteraction with fluoxetine.