Predictors of Antidepressant Response

NCT ID: NCT02178696

Last Updated: 2017-12-05

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 44 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-01-31
• Study Completion Date: 2015-10-31

Brief Summary

Major depression is a highly prevalent, frequently debilitating illness that too often fails to respond to currently available treatments such as antidepressant medication. Furthermore, randomized controlled trials of antidepressants consistently demonstrate large placebo effects. The investigators hypothesize that individual differences in the function of key brain circuits underlie the observed variability in clinical responses to both placebo and antidepressant medication. This study will test this hypothesis by recruiting treatment-seeking volunteers with major depression, with or without comorbid nicotine dependence. Volunteers will participate in positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) scans in the context of a treatment trial in which they will receive both placebo and antidepressant medication. A major goal of the study is to improve prediction of individual clinical responses in future treatment trials in which brain imaging may be unavailable, and to study the mechanisms of antidepressant response in Major Depression.

Detailed Description

We performed a single-blinded two-week cross-over randomized controlled trial of two identical oral placebos (described as having either potentially "active" fast-acting antidepressant-like effects or to be "inactive") followed by a 10-week open-label treatment with a selective serotonin reuptake inhibitor (SSRI) or in some cases, another agent as clinically indicated. The volunteers were studied with PET and the µ-opioid receptor selective radiotracer [11C]carfentanil after each 1-week "inactive" and "active" oral placebo treatment. In addition, 1 mL of isotonic saline was administered intravenously (i.v.) within sight of the volunteer during PET scanning every 4 min over 20 min only after the 1-week active placebo treatment, with instructions that the compound may be associated with the activation of brain systems involved in mood improvement. This challenge stimulus was utilized to test the individual capacity to acutely activate endogenous opioid neurotransmission under expectations of antidepressant effect.

Conditions

Depression

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: OTHER
• Blinding Strategy: SINGLE

Study Groups

Known Placebo First

This arm gets a placebo that they know is a placebo (called inactive), then has 2 scans performed (FMRI and PET), then a 2-3 day washout, and then gets a so-called "active medication" (which is also actually a placebo), and another pair of scans. Following these, participants receive 10 weeks of open-label antidepressant administration (Celexa or alternative as explained in intervention description). First line antidepressant will be Celexa unless not clinically indicated.

Group Type: EXPERIMENTAL

Placebo, identified as placebo to participants

Intervention Type: OTHER

White tablets

Celexa or other antidepressant as clinically indicated

Intervention Type: DRUG

Open label s-citalopram, 20 mg start up dose, increasing to 40 mg as clinically indicated; If prior non-response to this medication is noted by the patient, alternative treatments may include another first-line antidepressant:fluoxetine 20 mg; paroxetine up to 60 mg; sertraline up to 200 mg; bupropion up to 300 mg

Placebo, identifed to participants as "Active medication"

Intervention Type: OTHER

Blue Capsule

"Active" (blinded) Placebo first group

This arm gets a placebo that they don't know is a placebo (called Active), then has 2 scans performed (FMRI and PET), then a 2-3 day washout, and then gets a so-called "inactive medication" (which participants know is a placebo), and another pair of scans. Following these, participants receive 10 weeks of open-label antidepressant administration (Celexa as explained in intervention description). First line antidepressant will be Celexa unless not clinically indicated.

Group Type: EXPERIMENTAL

Placebo, identified as placebo to participants

Intervention Type: OTHER

White tablets

Celexa or other antidepressant as clinically indicated

Intervention Type: DRUG

Open label s-citalopram, 20 mg start up dose, increasing to 40 mg as clinically indicated; If prior non-response to this medication is noted by the patient, alternative treatments may include another first-line antidepressant:fluoxetine 20 mg; paroxetine up to 60 mg; sertraline up to 200 mg; bupropion up to 300 mg

Placebo, identifed to participants as "Active medication"

Intervention Type: OTHER

Blue Capsule

Interventions

Placebo, identified as placebo to participants

White tablets

Intervention Type: OTHER

Celexa or other antidepressant as clinically indicated

Open label s-citalopram, 20 mg start up dose, increasing to 40 mg as clinically indicated; If prior non-response to this medication is noted by the patient, alternative treatments may include another first-line antidepressant:fluoxetine 20 mg; paroxetine up to 60 mg; sertraline up to 200 mg; bupropion up to 300 mg

Intervention Type: DRUG

Placebo, identifed to participants as "Active medication"

Blue Capsule

Intervention Type: OTHER

Other Intervention Names

S-citalopram 20-40 mg orally

Eligibility Criteria

Inclusion Criteria

• Participants diagnosed with Major Depressive Disorder and will include Hamilton Depressive Rating Scale (HDRS) scores >15

Exclusion Criteria

• Comorbid conditions that are medical, neurological or psychiatric, pregnancy, use of hormones (including birth control) or use of psychotropic agents
• We will only permit certain past anxiety disorder diagnoses, including generalized anxiety, panic, agoraphobia, social phobia
• We also will exclude left-handed individuals and patients who have used any centrally acting medications or recreational drugs with the past 2 months
• No history of an implant, pacemaker or pacemaker wires, open heart surgery, artificial heart valve, brain aneurysm surgery, middle ear implant, hearing aid, braces or extensive dental work, cataract surgery or lens implant, implanted mechanical or electrical device, or artificial limb or joint
• No metallic object in their body (such as braces) or have a history of foreign metallic object in the body such as bullets, BB's, pellets, shrapnel, or other metal fragments

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of Michigan

OTHER

Sponsor Role: lead

Responsible Party

Jon-Kar Zubieta

MD PhD

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Jon-Kar Zubieta, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

University of Michigan

Locations

Department of Psychiatry

Ann Arbor, Michigan, United States

Countries

United States

References

Pecina M, Bohnert AS, Sikora M, Avery ET, Langenecker SA, Mickey BJ, Zubieta JK. Association Between Placebo-Activated Neural Systems and Antidepressant Responses: Neurochemistry of Placebo Effects in Major Depression. JAMA Psychiatry. 2015 Nov;72(11):1087-94. doi: 10.1001/jamapsychiatry.2015.1335.

Reference Type: RESULT

PMID: 26421634 (View on PubMed)

Sikora M, Heffernan J, Avery ET, Mickey BJ, Zubieta JK, Pecina M. Salience Network Functional Connectivity Predicts Placebo Effects in Major Depression. Biol Psychiatry Cogn Neurosci Neuroimaging. 2016 Jan;1(1):68-76. doi: 10.1016/j.bpsc.2015.10.002.

Reference Type: RESULT

PMID: 26709390 (View on PubMed)

Other Identifiers

HUM00033328

Identifier Type: -

Identifier Source: org_study_id