Fluoxetine Treatment of Depression in Down Syndrome

After being informed about the study and potential risks, all patients or their legal guardians giving written informed consent will be screened for study eligibility. Patients who meet the eligibility requirements will participate in a 16-week, flexibly-dosed, open-label trial of fluoxetine. The dose of fluoxetine will be adjusted over the first 12 weeks of the study and a stable dose will be maintained for the final four weeks of the trial. Adverse effects will be reviewed at each visit and standardized measures of depression will be conducted at weeks 4, 8, 12, and 16.

Inclusion criteria

• Age 18-45 years.
• Diagnosis of DS confirmed via genetic testing or a clinical diagnosis made by a clinician with significant experience treating patients with DS.
• Diagnosis of major depressive disorder based on Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria, confirmed through the Structured Clinical Interview for DSM-5 (SCID-5).
• Moderately severe depression as evidenced by a Montgomery-Asberg Depression Rating Scale (MADRS) score of 20 or greater at Screen and Baseline. A severity score on the MADRS was chosen as an inclusion criterion since it has been demonstrated to be sensitive to change in adults with MDD.
• A Clinical Global Impression Severity Item score > 4 (moderate) for depression symptoms at Screen and Baseline.

Exclusion criteria

• Active primary diagnosis of obsessive-compulsive disorder, posttraumatic stress disorder, bipolar disorder, psychosis, or substance use disorder. These disorders are exclusionary since the primary treatment of these disorders may require acute psychosocial or medication treatments that would confound the assessments used in this study. We will evaluate for these disorders using the corresponding SCID-5 modules.
• Current or previous diagnosis of dementia, or use of medication to treat dementia. Given the potential overlap between depression and dementia symptoms, we want to ensure we are administering fluoxetine to patients with a diagnosis of depression.
• Presence of any past or present conditions that would make treatment with fluoxetine unsafe. This includes allergy to fluoxetine, liver or kidney disease, unstable heart disease, and/or pregnancy (or being sexually active without using acceptable methods to prevent pregnancy).
• Use of selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), bupropion, mirtazapine, antipsychotics, lithium, valproic acid, or carbamazepine. Subjects will need to be off these classes of medications for at least 5 elimination half-lives prior to beginning the trial.
• Use of other psychotropic medications which are ineffective, poorly tolerated, or sub-optimal in terms of dose. A board-certified psychiatrist will assess any other psychotropic medications being used and determine whether they are effective, tolerated, and optimal in terms of dose. If medications are ineffective, poorly tolerated, or sub-optimal in terms of dose, the study psychiatrist will work with the subject and his/her treatment team to either taper or optimize the dose of psychotropic medications prior to study enrollment. Concurrent use of a psychotropic medication (other than SSRIs, SNRIs, TCAs, MAOIs, bupropion, mirtazapine, antipsychotics, lithium, valproic acid, or carbamazepine) will be allowed if the dose has been stable for 30 days and if they meet the criteria of effectiveness, tolerability, and dose.
• Previous adequate trial of fluoxetine. An adequate trial will be defined as a total daily dose of ≥30 mg for at least 4 weeks. In addition, subjects who developed significant adverse effects during a trial of fluoxetine at any dose or duration will be excluded.
• Severe or profound intellectual disability based on clinical assessment and review of standardized assessment of cognitive skills. Participants determined to have severe or profound intellectual disability will be excluded.
• Use of medications that pose a clinically significant risk of a drug-drug interaction with fluoxetine.