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Imaging Dopamine Release in Depression

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ClinicalTrials.gov Identifier: NCT02033369
Recruitment Status : Completed
First Posted : January 10, 2014
Results First Posted : November 21, 2017
Last Update Posted : December 18, 2018
Sponsor:
Collaborators:
Columbia University
Research Foundation for Mental Hygiene, Inc.
Mclean Hospital
Icahn School of Medicine at Mount Sinai
National Institute of Mental Health (NIMH)
Information provided by (Responsible Party):
Franklin Schneier, New York State Psychiatric Institute

Brief Summary:
This study aims to determine whether ventral striatal dopamine release is a mechanism of reward motivation in major depression, whether dopamine release is low in depression, and whether DA release and reward motivation predict response to dopamine-targeted treatment with pramipexole.

Condition or disease Intervention/treatment Phase
Major Depressive Disorder Drug: Pramipexole Phase 4

Detailed Description:
Better understanding of the basic neurobiology of mood dysfunction appears necessary to enable further progress in the treatment of depression. Reward motivation (and the closely related construct of "reward learning") is a core neurobehavioral domain.(1,2) In major depressive disorder (MDD), low reward motivation is a key aspect of anhedonia, a cardinal symptom of MDD, and is related to resistance to treatment.(2,3) Although much has been learned about reward motivation's neurobiology and relevance to psychopathology, important gaps in our knowledge have impeded the application of basic science findings to improving treatment of MDD. Reward motivation in healthy subjects involves ventrostriatal (VST) dopamine (DA)(4,5), and reduced reward motivation is linked to MDD and anhedonia.(3,6) These data suggest that VST DA dysfunction might be present in MDD and manifested clinically by anhedonia. While DA neuroreceptor imaging studies have failed to verify this, they have been methodologically compromised. Limitations include imaging methods with poor resolution of functional striatal subregions, MDD samples heterogeneous for antidepressant use, and use of self-report measures of anhedonia, rather than objective behavioral testing of the specific domain of reward motivation. This will be the first study of both VST DA release (by PET imaging) and reward motivation, and will include patients with MDD and healthy volunteers. Reward motivation will be captured and operationalized as reward learning in a probabilistic reward task (prior to imaging). This will clarify if VST DA dysfunction is linked to impaired motivation in MDD. To test clinical implications in MDD patients, we will assess the relationship of VST DA release, reward motivation, and anhedonia to outcome of subsequent open label treatment with the DA D2 receptor agonist pramipexole.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 52 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Other
Official Title: Ventrostriatal Dopamine Release and Reward Motivation in MDD
Actual Study Start Date : February 2014
Actual Primary Completion Date : December 2016
Actual Study Completion Date : July 2017

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Pramipexole
Six weeks of treatment with oral pramipexole, initiated at 0.25 mg/day and titrated to a maximum daily dose of 2.5 mg.
Drug: Pramipexole
Dose will be started at 0.125 mg bid, and increased by 0.25 mg/day every 3-4 days to a target range of 1.0 - 2.5 mg/day.
Other Name: Mirapex (brand name)

No Intervention: Healthy Control
Healthy volunteers were matched to MDD group subjects by age, gender, and ethnicity, and will have no lifetime psychiatric disorders.



Primary Outcome Measures :
  1. Change in Hamilton Rating Scale for Depression [ Time Frame: Baseline and 6 weeks ]
    Hamilton Rating Scale for Depression (HRSD), 17-item version. This standard scale will be used to assess severity of depression, looking at change in total score from baseline to week 6, rating severity of depression on a scale from 0 (least depression) to 50 (greatest depression)


Secondary Outcome Measures :
  1. Change in Snaith Hamilton Pleasure Scale [ Time Frame: Baseline and 6 weeks ]
    Fourteen-item self-rated anhedonia scale. Items were comprised of statements that participants rated as "strongly disagree" (1), "disagree" (2), "agree" (3), or "strongly agree" (4). The lowest possible score was 14, the highest possible score was 56.

  2. Change in Temporal Experience of Pleasure Scale - Anticipatory Subscale [ Time Frame: Baseline and 6 weeks ]

    A validated self-rated scale shown to assess anticipatory pleasure. It will be used for exploratory analyses of anhedonia.

    18 items were measured on a scale of 1 (very false for me) to 6 (very true for me). Higher scores indicate higher pleasure. Item scores were added for a lowest possible score of 18 and highest possible score of 108.


  3. Change in Mood and Anxiety Symptom Questionnaire, Short Form [ Time Frame: Baseline and 6 weeks ]
    Change in Mood and Anxiety Symptom Questionnaire, Short Form. A 62-item scale assessing anxiety and depression. Items were measured on a scale of 1-5, higher number indicating higher levels of symptoms.The lowest possible score was 62, and the highest 310.

  4. Change in the Apathy Evaluation Rating Scale [ Time Frame: Baseline and 6 weeks ]
    A validated self-rated 18 item scale assessing apathy. Items were rated from 1 (not at all true) to 4 (very true). Higher scores indicate lower apathy, lower scores indicate higher apathy. Lowest possible score is 18, highest possible score is 72.

  5. Change in Clinical Global Improvement - Severity Scale [ Time Frame: 6 weeks ]
    Seven-point Likert scale rating clinical severity of mental illness from 1 (least severe) to 7 ( most severe). Physician-rated scale. One item.

  6. Change in Temporal Experiences of Pleasure Scale -- Consummatory Subscale [ Time Frame: Baseline and 6 weeks ]

    A validated self-rated scale shown to assess consummatory pleasure. It will be used for exploratory analyses of anhedonia.

    18 items were measured on a scale of 1 (very false for me) to 6 (very true for me). Higher scores indicate higher pleasure. Item scores were added for a lowest possible score of 18 and highest possible score of 108.




Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 50 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Weight between 44 kg and 115 kg
  • Meets DSM-IV criteria for principal diagnosis of MDD, current major depressive episode, without psychotic features
  • Score of >16 and <29 on 17-item Hamilton Rating Scale for Depression
  • Psychotropic-naïve, as defined by lifetime <2 weeks treatment with antidepressants, anxiolytics or antipsychotics
  • Able to tolerate a treatment-free period during study participation
  • Able to provide informed consent

Exclusion Criteria:

  • A principal diagnosis of any current Axis I psychiatric disorder other than the MDD
  • Lifetime diagnosis of any psychotic disorder, bipolar disorder, mental retardation, attention deficit/hyperactivity disorder, or substance use disorders (including nicotine use disorders)
  • Serious suicidal risk or history of violent behavior which would make participation in the protocol unsafe
  • Any tobacco use in the prior three months (if not already excluded for abuse/dependence by #1)
  • Illicit drug use in the prior three months, as evidenced by history or urine toxicology screen
  • Women who are pregnant, nursing, postmenopausal, or using hormonal methods of birth control
  • Women who are not using an effective birth control method or sexual abstinence during the ten days before the scan
  • Any medical or neurological problem that might affect interpretation of findings or safety of participation (e.g., blood dyscrasias, lymphomas, hypersplenism, endocrinopathies, renal failure or chronic obstructive lung disease, malignancy, neurological diseases of the brain, history of seizures or head trauma), low hemoglobin (Hb < 12 gm/dL in males, Hb < 10.5 gm/dL in females))
  • Blood donation within 4 weeks of study
  • Metal implants or paramagnetic objects in the body that might affect safety of undergoing MRI (e.g., heart pacemaker, shrapnel, bullets, surgical prostheses or surgical clips), as determined in consultation with a neuroradiologist and according to the guidelines set forth in the reference: "Guide to MR procedures and metallic objects" Shellock; Lippincott Williams and Wilkins, NY, 2001
  • More than one major risk factor for coronary artery disease (e.g. hyperlipidemia, sedentary lifestyle). Smokers are already excluded by #4 above, and diabetics by #8 above
  • Systolic blood pressure > 140 or diastolic blood pressure > 90 based on at least two readings at rest
  • History of untoward reaction to amphetamine or other stimulant medication, or pramipexole
  • Any psychotropic treatment in the past 3 weeks (or depot medication in the past 6 months), except for lorazepam,which may be administered as needed prior to imaging day
  • Current, past or anticipated exposure to radiation in the workplace, or participation in nuclear medicine procedures, including research protocols (In case of previous exposure to activity due to research studies, subjects will be eligible if all conditions listed below are fulfilled: 1) The injected dose and dosimetry of the radiotracer are known; 2) Except for research studies, the subject has not been exposed to radiation (workplace and medical); 3) Adding prior exposure to the exposure due to the study will result in a yearly cumulative exposure lower than the FDA limit for research studies
  • Family history of schizophrenia in parents, siblings, or children
  • Ongoing cognitive-behavioral or interpersonal psychotherapy for depression (Supportive therapy is not an exclusion)
  • Ongoing treatment with cimetidine

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02033369


Locations
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United States, New York
New York State Psychiatric Institute
New York, New York, United States, 10032
Sponsors and Collaborators
New York State Psychiatric Institute
Columbia University
Research Foundation for Mental Hygiene, Inc.
Mclean Hospital
Icahn School of Medicine at Mount Sinai
National Institute of Mental Health (NIMH)
Investigators
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Principal Investigator: Franklin Schneier, MD NYSPI

Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Franklin Schneier, Professor, New York State Psychiatric Institute
ClinicalTrials.gov Identifier: NCT02033369     History of Changes
Other Study ID Numbers: #6853
1R01MH099322-01A1 ( U.S. NIH Grant/Contract )
First Posted: January 10, 2014    Key Record Dates
Results First Posted: November 21, 2017
Last Update Posted: December 18, 2018
Last Verified: November 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by Franklin Schneier, New York State Psychiatric Institute:
Major depressive disorder
MDD
depression
pramipexole
Additional relevant MeSH terms:
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Depressive Disorder
Depression
Depressive Disorder, Major
Mood Disorders
Mental Disorders
Behavioral Symptoms
Dopamine
Pramipexole
Cardiotonic Agents
Sympathomimetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Dopamine Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Protective Agents
Antioxidants
Antiparkinson Agents
Anti-Dyskinesia Agents
Dopamine Agonists