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Major Depressive Disorder | Dopaminergic Effects of Adjunctive Aripiprazole on the Brain in Treatment-Resistant Depression

Major Depressive Disorder research study

What is the primary objective of this study?

Aripiprazole has been approved by the FDA for augmenting ineffective/partially effective oral antidepressant therapy in patients suffering from major depression. The mechanism by which this augmentation is achieved is not known. This study has been designed to test the hypothesis that the primary mechanism of action of aripiprazole (ARP) antidepressant augmentation is through the dopaminergic pathway. Two positron emission tomography (PET) scan procedures and a functional magnetic resonance imaging (fMRI) scan will be used to test this hypothesis.

Who is eligible to participate?

Treatment Group Inclusion Criteria: 1. Subjects with known history of MDD verified using the Mini International Neuropsychiatric Interview and a Hamilton Depression Rating Scale 17-item score of at least 18 2. Subjects must have failed to respond to one previous adequate dose-duration trial of antidepressant therapy 3. Must complete the MRI screening tool and demonstrate ability to receive an MRI 4. For entry into the ARP augmentation phase the subject must be a non-responder to the escitalopram phase as demonstrated by a MADRS score at week 10, that is not reduced by greater than 50% from baseline. Exclusion Criteria: 1. Subjects cannot be smokers 2. No significant history of anxiety disorder 3. Cannot be pregnant or lactating and sexually active women of childbearing potential must use a medically accepted means of contraception 4. The following DSM-IV diagnoses are excluded: Organic mental disorder; substance abuse/dependence, including alcohol, active within the last year; schizophrenia, paranoid or delusional disorders; other psychotic disorders; panic disorder; generalized anxiety disorder; obsessive-compulsive disorder, or post-traumatic stress disorder; bipolar disorder; bulimia nervosa; anorexia nervosa 5. Subjects with serious suicidal risks 6. Subjects who have taken any antidepressant medication other than escitalopram within 5 half lives, of the most recent antidepressant taken 7. Subjects involved in any other form of treatment for depression 8. Subjects who have demonstrated any previous inadequate antidepressant response to electroconvulsive therapy (ECT) 9. Subjects who have received ECT for the current depression episode 10. Subjects who have been hospitalized within 4 weeks of the study 11. Subjects who have received treatment with a monoaminoxidase inhibitor within 2 weeks of enrollment 12. Subjects with a known allergy, hypersensitivity, or previous unresponsiveness to aripiprazole or known intolerance to any study medications 13. Subjects with a history of participation in any investigational medication trial in the past month 14. A positive drug screen or substance use disorder in the past 12 months 15. History of any thyroid pathology 16. History of serotonin syndrome or neuroleptic malignant syndrome 17. History of seizure disorder 18. Subjects who have participated in a trial using PET scans in the past 12 months and in any trial in the past 30 days. Control Group Inclusion Criteria: 1. Ages 18-55 matched to a study subject 2. Must be a healthy subject with no significant medical history 3. Must complete the MRI screening tool and demonstrate ability to receive an MRI Exclusion Criteria: 1. Cannot be a smoker 2. Cannot be pregnant or lactating and sexually active women of childbearing potential must use a medically accepted means of contraception 3. Any DSM-IV or II diagnosis as assessed by the MINI 4. Subjects with a positive drug screen or substance use disorder in the past 12 months

Which medical condition, disease, disorder, syndrome, illness, or injury is researched?

Major Depressive Disorder

Study Interventions

Interventions can include giving participants drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available or noninvasive approaches such as surveys, education, and interviews.

Drug:EscitalopramAll subjects will begin on escitalopram and placebo for 8 weeks

Drug:AripiprazoleSubjects who fail to respond to Escitalopram will continue on Escitalopram and augment with active Aripiprazole.

Drug:Placebo CapsuleAll subjects will begin on escitalopram and placebo capsule for 8 weeks.

Drug:Placebo TabletAfter 8 weeks, subjects will be given a 2 week supply of escitalopram and placebo tablet.

Study Arms

Research studies and clinical trials typically have two or more research arms. An arm is a group of people who receive the same treatment in the study.

Depressed ParticipantsSubjects with treatment-resistant depression (TRD) will be administered the Hamilton Depression Rating Scale (HAM-D 17) for entry and will receive escitalopram combined with an adjunctive placebo capsule for 8 weeks. Subjects who fail to respond will continue to receive escitalopram and additionally change to receive a placebo tablet resembling the active augmentation agent Aripiprazole (ARP) for 2 weeks. Subjects who fail to respond to escitalopram after the 2 phase placebo treatment will enter the ARP augmentation phase of the study and will receive escitalopram augmentation with ARP. Subjects will have 3 neuroimaging scans: F-DOPA PET, raclopride PET, and functional MRI conducted after 10 weeks of treatment and repeated after 6 weeks of ARP treatment.

Control ParticipantsNon-depressed, age- and sex-matched subjects without a DSM-IV Axis I diagnosis will serve as controls. They will not receive antidepressant, ARP, or any drug augmentation and will be used as quality control to compare the pre-ARP and post-ARP treatment brain images.

Study Status

Completed

Start Date: May 2009

Completed Date: December 2012

Phase: N/A

Type: Interventional

Design:

Primary Outcome: Fluorodopa Uptake Values in Brain Images of Aripiprazole Augmentation Responders

Secondary Outcome: Depression Symptom Change on The Montgomery-├ůsberg Depression Rating (MADRS) Scale Between ARP Responders and Non-responders.

Study sponsors, principal investigator, and references

Principal Investigator: Charles R Conway, MD

Lead Sponsor: Washington University School of Medicine

Collaborator: Bristol-Myers Squibb

More information:https://clinicaltrials.gov/show/NCT00953745

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